MND Research Update
Ref ID 1
Authors : Anonymous
Title : Motor neuron disease: Serum N-acetylaspartate: a potential biomarker for amyotrophic lateral sclerosis?
Journal : Nat.Rev.Neurol. 2011 vol.8 part 1 pp 3Language : eng
Ref ID 2
Authors : J. Aebischer, A. Moumen, V. Sazdovitch, D. Seilhean, V. Meininger and C. Raoul.
Title : Elevated levels of IFNgamma and LIGHT in the spinal cord of patients with sporadic amyotrophic lateral
sclerosis
Journal : Eur.J.Neurol. 2012
Abstract : Background: Amyotrophic lateral sclerosis (ALS) is a paralytic and fatal neurodegenerative disorder
caused by the gradual loss of both upper and lower motoneurons. There is compelling evidence from ALS
experimental models that neuroinflammation actively contributes to motoneuron damage. We recently proposed
that interferon gamma (IFNgamma), a potent proinflammatory cytokine, induces motoneuron death by eliciting
the activation of the lymphotoxin beta receptor (LT-betaR) through its ligand LIGHT. Here, we explore the
pertinence of this non-cell-autonomous mechanism in human ALS. Methods: The levels and expression pattern of
IFNgamma, LIGHT, and LT-betaR were investigated by Western blot and immunohistochemical analysis in spinal
cord of patients with sporadic ALS. Results: We observed significant increased levels of IFNgamma in human ALS
spinal cords compared to control cases. We found that large ventral horn neurons as well as glial cells were
immunoreactive for IFNgamma in sporadic ALS spinal cord. We further observed that LIGHT and LT-betaR were
expressed mainly by motoneurons in both ALS and control cases, and while LT-betaR levels remained constant
between ALS and control cases, LIGHT levels were increased in human ALS spinal cords. Conclusion: These
findings in sporadic ALS cases, which are consistent with the observation made in ALS experimental models,
propose that the IFNgamma-triggered LIGHT/LT-betaR-mediated death pathway may contribute to human ALS
pathogenesis.
Language : ENG
Ref ID 3
Authors : P. L. Andres, L. M. Skerry, T. L. Munsat, et al.
Title : Validation of a new strength measurement device for amyotrophic lateral sclerosis clinical trials
Journal : Muscle Nerve 2012 vol.45 part 1 pp 81-85
Abstract : INTRODUCTION: Strength measures with reduced variability and higher sensitivity could improve
efficiency in clinical trials of amyotrophic lateral sclerosis (ALS). The Accurate Test of Limb Isometric Strength
(ATLIS) was developed to precisely and conveniently measure force in 12 muscle groups. In this study we
evaluate the reliability and validity of the ATLIS testing protocol. METHODS: Twenty healthy adults and 10 patients
with ALS were tested twice by the same or by different evaluators to determine test-retest and interrater
reliability. Twenty healthy adults were examined using ATLIS and a well-validated strength testing protocol (TQNE)
to assess criterion-based validity. RESULTS: Mean absolute variation between tests was 8.6%, and intraclass
correlation coefficients for each muscle group were high (range 0.82-0.99). The Pearson correlation coefficient of
mean ATLIS and TQNE scores was 0.90. A subject survey demonstrated high user acceptance of ATLIS.
CONCLUSIONS: ATLIS is convenient for patients and evaluators, produces precise strength measurements, and is
easily moved between examining rooms. Muscle Nerve 45: 81-85, 2012.
Language : eng
Ref ID 4
Authors : K. Aoyama, F. Wang, N. Matsumura, et al.
Title : Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice
Journal : Neurobiol.Dis. 2011
Abstract : Glutathione (GSH) is an important neuroprotective molecule in the brain. The strategy to increase
neuronal GSH level is a promising approach to the treatment of neurodegenerative diseases. However, the
regulatory mechanism by which neuron-specific GSH synthesis is facilitated remains elusive. Glutamate
transporter-associated protein 3-18 (GTRAP3-18) is an endoplasmic reticulum protein interacting with excitatory
amino acid carrier 1 (EAAC1), which is a neuronal glutamate/cysteine transporter. To investigate the potential
regulatory mechanism to increase neuronal GSH level in vivo, we generated GTRAP3-18-deficient (GTRAP3-18(-/)) mice using a gene-targeting approach. Disruption of the GTRAP3-18 gene resulted in increased EAAC1
expression in the plasma membrane, increased neuronal GSH content and neuroprotection against oxidative
stress. In addition, GTRAP3-18(-/-) mice performed better in motor/spatial learning and memory tests than wildtype mice. Therefore, the suppression of GTRAP3-18 increases neuronal resistance to oxidative stress by
increasing GSH content and also facilitates cognitive function. The present results may provide a molecular basis
for the development of treatments for neurodegenerative diseases.
Language : ENG
Ref ID 5
Authors : M. Arrasate and S. Finkbeiner.
Title : Protein aggregates in Huntington's disease
Journal : Exp.Neurol. 2011
Abstract : Huntington's disease (HD) is an incurable neurodegenerative disease characterized by abnormal motor
movements, personality changes, and early death. HD is caused by a mutation in the IT-15 gene that expands
abnormally the number of CAG nucleotide repeats. As a result, the translated protein huntingtin contains diseasecausing expansions of glutamines (polyQ) that make it prone to misfold and aggregate. While the gene and
mutations that cause HD are known, the mechanisms underlying HD pathogenesis are not. Here we will review the
state of knowledge of HD, focusing especially on a hallmark pathological feature-intracellular aggregates of mutant
Htt called inclusion bodies (IBs). We will describe the role of IBs in the disease. We speculate that IB formation
could be just one component of a broader coping response triggered by misfolded Htt whose efficacy may depend
on the extent to which it clears toxic forms of mutant Htt. We will describe how IB formation might be regulated
and which factors could determine different coping responses in different subsets of neurons. A differential
regulation of IB formation as a function of the cellular context could, eventually, explain part of the neuronal
vulnerability observed in HD.
Language : ENG
Ref ID 6
Authors : J. N. Audet, G. Soucy and J. P. Julien.
Title : Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse
models
Journal : Neuroscience 2012
Abstract : Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the
gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was
efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial
function, to reduce ROS, to clear aggregates of toxic proteins, and to act as a NO synthase inhibitor. These
pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and
TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the
beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice.
Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS.
The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score,
and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and
aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A)
mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43,
ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.
Language : ENG
Ref ID 7
Authors : C. Barinka, C. Rojas, B. Slusher and M. Pomper.
Title : Glutamate Carboxypeptidase II in Diagnosis and Treatment of Neurologic Disorders and Prostate Cancer
Journal : Curr.Med.Chem. 2012
Abstract : Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the
highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound
GCPII is intimately involved in the neuronneuron and neuron-glia signaling via the hydrolysis of Nacetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the
GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate
transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic
brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The
second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII
expression levels are highly increased in androgenindependent and metastatic disease. Consequently, the enzyme
serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure,
physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the
development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.
Language : ENG
Ref ID 8
Authors : A. H. Batcha, U. Greferath, A. I. Jobling, et al.
Title : Retinal dysfunction, photoreceptor protein dysregulation and neuronal remodelling in the R6/1 mouse model
of Huntington's disease
Journal : Neurobiol.Dis. 2011
Abstract : Huntington's disease (HD) is a progressive neurological disease characterised by motor dysfunction,
cognitive impairment and personality changes. Previous work in HD patients and animal models of the disease has
also highlighted retinal involvement. This study characterised the changes in retinal structure and function early
within the progression of disease using the R6/1 mouse model of HD. The retinal phenotype was observed to occur
at the same time in the disease process as other neurological deficits such as motor dysfunction (by 13weeks of
age). There was a specific functional deficit in cone response to the electroretinogram and using
immunocytochemical techniques, this dysfunction was found to be likely due to a progressive and complete loss of
cone opsin and transducin protein expression by 20weeks of age. In addition, there was an increase in Muller cell
gliosis and the presence of ectopic rod photoreceptor terminals. This retinal remodelling is also observed in
downstream neurons, namely the rod and cone bipolar cells. While R6/1 mice exhibit significant retinal pathology
simultaneously with other more classical HD alterations, this doesn't lead to extensive cell loss. These findings
suggest that in HD, cone photoreceptors are initially targeted, possibly via dysregulation of protein expression or
trafficking and that this process is subsequently accompanied by increased retinal stress and neuronal remodelling
also involving the rod pathway. As retinal structure and connectivity are well characterised, the retina may provide
a useful model tissue in which to characterise the mechanisms important in the development of neuronal
pathology in HD.
Language : ENG
Ref ID 9
Authors : J. Brettschneider, D. J. Libon, J. B. Toledo, et al.
Title : Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral
sclerosis
Journal : Acta Neuropathol. 2012
Abstract : While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral
sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of
neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically
analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68,
Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and
neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex)
patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus
regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of
executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's
disease (AD) pathology. Tau and Abeta pathology increased with age. A lower MMSE score correlated with tau
pathology in hippocampus and SMT gyrus, and with Abeta pathology in limbic and most cortical regions. Tau and
Abeta pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43
pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with
neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to
increasing age and associated with a poorer performance on the MMSE.
Language : ENG
Ref ID 10
Authors : A. Bruson, F. Sambataro, G. Querin, et al.
Title : CAG repeat length in androgen receptor gene is not associated with amyotrophic lateral sclerosis
Journal : Eur.J.Neurol. 2012
Abstract : Background: Epidemiological and clinical studies show higher prevalence of amyotrophic lateral sclerosis
(ALS) in males than in females and more severe lesions in androgen receptor (AR)-expressing tissues. The AR
gene contains a polymorphic CAG trinucleotide repeat, whose expansion over a certain threshold is toxic to motor
neurons, causing spinal and bulbar muscular atrophy (SBMA). Purpose and methods: We tested the hypothesis
that the AR CAG repeat linked to SBMA is a risk factor for ALS. We analyzed AR CAG expansions in 336 patients
with ALS and 100 controls. Results: We found a negative association of AR CAG expansions with ALS susceptibility,
clinical presentation, and survival. Conclusions: Our findings do not support a role of the AR CAG repeat length in
ALS.
Language : ENG
Ref ID 11
Authors : T. A. Caller, N. C. Field, J. W. Chipman, X. Shi, B. T. Harris and E. W. Stommel.
Title : Spatial clustering of amyotrophic lateral sclerosis and the potential role of BMAA
Journal : Amyotroph Lateral Scler. 2012 vol.13 part 1 pp 25-32
Abstract : Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome which has no known
cause, except for a small proportion of cases which are genetically inherited. The development of ALS likely
involves both genetic and environmental risk factors. Environmental risk factors implicated in ALS have included
heavy metals, trauma, pesticides, electrical injuries, electromagnetic radiation and the cyanobacterial-derived
neurotoxin beta-N-methylamino-L-alanine (BMAA). To investigate possible environmental risks, a number of
epidemiological studies of ALS have been conducted. Some of these studies employ spatial analysis techniques
that examine for spatial clusters of ALS and can help guide further research into identifying environmental
exposures. Despite identifying geographical disparities in the distribution of ALS cases, these studies have not
provided any clear associations with environmental factors. We review the literature on important studies of
spatial clustering of ALS and explore the hypothesized link between the neurotoxin BMAA and ALS.
Language : eng
Ref ID 12
Authors : G. Carrara, C. Carapelli, F. Venturi, et al.
Title : A Distinct MR Imaging Phenotype in Amyotrophic Lateral Sclerosis: Correlation between T1 Magnetization
Transfer Contrast Hyperintensity along the Corticospinal Tract and Diffusion Tensor Imaging Analysis
Journal : AJNR Am.J.Neuroradiol. 2011
Abstract : BACKGROUND AND PURPOSE:In the search for a diagnostic marker in ALS, we focused our attention on
the hyperintense signal intensity in T1 MTC MR images along the CST, detected in some patients and not found in
other patients with ALS and in control subjects. The aim of this study was to investigate the relationship between
the hyperintense signal intensity in T1 MTC images and white matter damage. To this purpose, we studied
potential heterogeneities in DTI values within our patients by using TBSS without a priori anatomic
information.MATERIALS AND METHODS:In 43 patients with ALS and 43 healthy control subjects, the presence or
absence of T1 MTC hyperintense signal intensity was evaluated. With a DTI analysis with a TBSS approach,
differences in FA distribution between the 2 groups (patients with T1 MTC hyperintense signal intensity and
patients without it) compared with each other and with control subjects were investigated.RESULTS:We found
regional differences in white matter FA between patients with T1 MTC hyperintense signal intensity (37.2%) and
patients without it. Patients with T1 MTC abnormal signal intensity showed lower FA strictly limited to the motor
network and the posterior aspect of the body of the CC without extramotor FA reductions, whereas patients
without this sign showed FA reductions in several confluent regions within and outside the CST and in the whole
CC.CONCLUSIONS:T1 MTC hyperintense signal intensity in the CST and posterior CC, when present, is specific for
ALS and represents, among patients with ALS, a possible distinct phenotype of presentation of the disease with
prominent UMN involvement.
Language : ENG
Ref ID 13
Authors : L. Chen, H. Xi and H. Huang.
Title : Cell-Based Neurorestorotherapy in Amyotrophic Lateral Sclerosis - Scientific Truth should Rely on Facts, but
Not Conjecture
Journal : Front.Integr.Neurosci. 2011 vol.5 pp 83Language : eng
Ref ID 14
Authors : T. Chen, R. Benmohamed, J. Kim, et al.
Title : ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide
Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic
Lateral Sclerosis
Journal : J.Med.Chem. 2011
Abstract : Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure.
The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high
throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and
aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties
but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe
synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and
pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the
corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro
pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an
ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the
mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic
lead for the treatment of this neurodegenerative disorder.
Language : ENG
Ref ID 15
Authors : I. Choi, H. D. Song, S. Lee, et al.
Title : Direct observation of defects and increased ion permeability of a membrane induced by structurally
disordered cu/zn-superoxide dismutase aggregates
Journal : PLoS One 2011 vol.6 part 12 pp e28982
Abstract : Interactions between protein aggregates and a cellular membrane have been strongly implicated in
many protein conformational diseases. However, such interactions for the case of Cu/Zn superoxide dismutase
(SOD1) protein, which is related to fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS), have not
been explored yet. For the first time, we report the direct observation of defect formation and increased ion
permeability of a membrane induced by SOD1 aggregates using a supported lipid bilayer and membrane patches
of human embryonic kidney cells as model membranes. We observed that aggregated SOD1 significantly induced
the formation of defects within lipid membranes and caused the perturbation of membrane permeability, based on
surface plasmon resonance spectroscopy, atomic force microscopy and electrophysiology. In the case of apo SOD1
with an unfolded structure, we found that it bound to the lipid membrane surface and slightly perturbed
membrane permeability, compared to other folded proteins (holo SOD1 and bovine serum albumin). The changes
in membrane integrity and permeability were found to be strongly dependent on the type of proteins and the
amount of aggregates present. We expect that the findings presented herein will advance our understanding of the
pathway by which structurally disordered SOD1 aggregates exert toxicity in vivo.
Language : eng
Ref ID 16
Authors : T. J. Cohen, A. W. Hwang, T. Unger, J. Q. Trojanowski and V. M. Lee.
Title : Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking
Journal : EMBO J. 2011
Abstract : TDP-43 is the major disease protein in ubiquitin-positive inclusions of amyotrophic lateral sclerosis and
frontotemporal lobar degeneration (FTLD) characterized by TDP-43 pathology (FTLD-TDP). Accumulation of
insoluble TDP-43 aggregates could impair normal TDP-43 functions and initiate disease progression. Thus, it is
critical to define the signalling mechanisms regulating TDP-43 since this could open up new avenues for
therapeutic interventions. Here, we have identified a redox-mediated signalling mechanism directly regulating
TDP-43. Using in vitro and cell-based studies, we demonstrate that oxidative stress promotes TDP-43 cross-linking
via cysteine oxidation and disulphide bond formation leading to decreased TDP-43 solubility. Biochemical analysis
identified several cysteine residues located within and adjacent to the second RNA-recognition motif that
contribute to both intra- and inter-molecular interactions, supporting TDP-43 as a target of redox signalling.
Moreover, increased levels of cross-linked TDP-43 species are found in FTLD-TDP brains, indicating that aberrant
TDP-43 cross-linking is a prominent pathological feature of this disease. Thus, TDP-43 is dynamically regulated by
a redox regulatory switch that links oxidative stress to the modulation of TDP-43 and its downstream targets.
Language : ENG
Ref ID 17
Authors : M. Cosottini, I. Pesaresi, S. Piazza, et al.
Title : Structural and functional evaluation of cortical motor areas in Amyotrophic Lateral Sclerosis
Journal : Exp.Neurol. 2011
Abstract : The structural and functional data gathered with Magnetic Resonance Imaging (MRI) techniques about
the brain cortical motor damage in Amyotrophic Lateral Sclerosis (ALS) are controversial. In fact some structural
MRI studies showed foci of gray matter (GM) atrophy in the precentral gyrus, even in the early stage, while others
did not. Most functional MRI (fMRI) studies in ALS reported hyperactivation of extra-primary motor cortices, while
contradictory results were obtained on the activation of the primary motor cortex. We aimed to investigate the
cortical motor circuitries in ALS patients by a combined structural and functional approach. Twenty patients with
definite ALS and 16 healthy subjects underwent a structural examination with acquisition of a 3D T1-weighted
sequence and fMRI examination during a maximal force handgrip task executed with the right-hand, the left-hand
and with both hands simultaneously. The T1-weighted images were analyzed with Voxel-Based Morphometry
(VBM) that showed several clusters of reduced cortical GM in ALS patients compared to controls including the pre
and postcentral gyri, the superior, middle and inferior frontal gyri, the supplementary motor area, the superior and
inferior parietal cortices and the temporal lobe, bilaterally but more extensive on the right side. In ALS patients a
significant hypoactivation of the primary sensory motor cortex and frontal dorsal premotor areas as compared to
controls was observed. The hypoactivated areas matched with foci of cortical atrophy demonstrated by VBM. The
fMRI analysis also showed an enhanced activation in the ventral premotor frontal areas and in the parietal cortex
pertaining to the fronto-parietal motor circuit which paralleled with disease progression rate and matched with
cortical regions of atrophy. The hyperactivation of the fronto-parietal circuit was asymmetric and prevalent in the
left hemisphere. VBM and fMRI identified structural and functional markers of an extended cortical damage within
the motor circuit of ALS patients. The functional changes in non-primary motor cortices pertaining to frontoparietal circuit suggest an over-recruitment of a pre-existing physiological sensory-motor network. However, the
concomitant fronto-parietal cortical atrophy arises the possibility that such a hyper-activation reflects cortical
hyper-excitability due to loss of inhibitory inter-neurons.
Language : ENG
Ref ID 18
Authors : J. P. de Almeida, R. Silvestre, A. C. Pinto and M. de Carvalho.
Title : Exercise and amyotrophic lateral sclerosis
Journal : Neurol.Sci. 2012
Abstract : Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease in which much
burden is geared towards end-of-life care. Particularly in the earlier stages of ALS, many people have found both
physiological and psychological boosts from various types of physical exercise for disused muscles. Proper exercise
is important for preventing atrophy of muscles from disuse-a key for remaining mobile for as long as possible-and
as long as it is possible to exercise comfortably and safely, for preserving cardiovascular fitness. However, the
typical neuromuscular patient features a great physical inactivity and disuse weakness, and for that reason many
controversial authors have contested exercise in these patients during years, especially in ALS which is rapidly
progressive. There is an urgent need for dissecting in detail the real risks or benefits of exercise in controlled
clinical trials to demystify this ancient paradigm. Yet, recent research studies document significant benefits in
terms of survival and quality of life in ALS, poor cooperation, small sample size, uncontrolled and short-duration
trials, remain the main handicaps. Sedentary barriers such as early fatigue and inherent muscle misuse should be
overcome, for instance with body-weight supporting systems or non-invasive ventilation, and exercise should be
faced as a potential non-monotonous way for contributing to better health-related quality of life.
Language : ENG
Ref ID 19
Authors : F. Ding, Y. Furukawa, N. Nukina and N. V. Dokholyan.
Title : Local Unfolding of Cu, Zn Superoxide Dismutase Monomer Determines the Morphology of Fibrillar
Aggregates
Journal : J.Mol.Biol. 2011
Abstract : Aggregation of Cu, Zn superoxide dismutase (SOD1) is often found in amyotrophic lateral sclerosis
patients. The fibrillar aggregates formed by wild type and various disease-associated mutants have recently been
found to have distinct cores and morphologies. Previous computational and experimental studies of wild-type
SOD1 suggest that the apo-monomer, highly aggregation prone, displays substantial local unfolding dynamics. The
residual folded structure of locally unfolded apoSOD1 corresponds to peptide segments forming the aggregation
core as identified by a combination of proteolysis and mass spectroscopy. Therefore, we hypothesize that the
destabilization of apoSOD1 caused by various mutations leads to distinct local unfolding dynamics. The partially
unfolded structure, exposing the hydrophobic core and backbone hydrogen bond donors and acceptors, is prone to
aggregate. The peptide segments in the residual folded structures form the "building block" for aggregation, which
in turn determines the morphology of the aggregates. To test this hypothesis, we apply a multiscale simulation
approach to study the aggregation of three typical SOD1 variants: wild type, G37R, and I149T. Each of these
SOD1 variants has distinct peptide segments forming the core structure and features different aggregate
morphologies. We perform atomistic molecular dynamics simulations to study the conformational dynamics of
apoSOD1 monomer and coarse-grained molecular dynamics simulations to study the aggregation of partially
unfolded SOD1 monomers. Our computational studies of monomer local unfolding and the aggregation of different
SOD1 variants are consistent with experiments, supporting the hypothesis of the formation of aggregation
"building blocks" via apo-monomer local unfolding as the mechanism of SOD1 fibrillar aggregation.
Language : ENG
Ref ID 20
Authors : E. M. Donnelly, E. Quach, T. Hillary, et al.
Title : Characterization of a murine model of SMA
Journal : Neurobiol.Dis. 2011
Abstract : Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, which is the leading
genetic cause of mortality in children. To date no effective treatment exists for SMA. The genetic basis for SMA has
been well documented as a mutation in the gene for survival of motor neuron (SMN). Because there is an
understanding of which gene needs to be replaced (SMN) and where it needs to be replaced (spinal motor
systems), SMA is an ideal target for gene replacement via gene therapy. While a variety of animal models for SMA
exist, they are either too fulminant to realistically test most gene delivery strategies, or too mild to provide a
robust read out of the therapeutic effect. The field, therefore, requires a robust model with a slower symptomatic
progression. A conditional knockout of SMN in neuronal cell types, giving a phenotype of functional motor defects,
weight loss and reduced life expectancy partially satisfies this need (Frugier, Tiziano et al. 2000). This Cre/LoxP
mediated neuron specific model presents an attractive alternative. In the present manuscript, we characterize the
functional motor deficits of the model. We observed a decline in locomotor ability, as assessed by open field
testing. The finer functions of motor skills such as righting reflex and grip strength were also observed to
degenerate in the SMA mice. The decline in motor function that we observed here correlates with the anatomical
decline in motor neurons and motor axons presented in the literature (Ferri, Melki et al. 2004). This work adds to
our understanding and knowledge base of this Cre/LoxP model and provides a basis from which functional
recovery, following interventions can be assessed.
Language : ENG
Ref ID 21
Authors : K. L. Double.
Title : Neuronal vulnerability in Parkinson's disease
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S52-4
Abstract : The classic motor symptoms of Parkinson's disease result from the progressive death of dopaminergic
neurons within the substantia nigra. To date the relatively selective vulnerability of this brain region is not
understood. The unique feature of dopaminergic neurons of the human substantia nigra pars compacta is the
presence of the polymer pigment neuromelanin which gives this region its characteristic dark colour. In the
healthy brain, neuromelanin appears to play a functional role to protect neurons from oxidative load but we have
shown that in the Parkinson's disease brain the pigment undergoes structural changes and is associated with
aggregation of alpha-synuclein protein, even early in the disease process. Further, the role of the pigment as a
metal binder has also been suggested to underlie the relative vulnerability of these neurons, as changes in metal
levels are suggested to be associated with neurodegenerative cascades in Parkinson's disease. While most
research to date has focused on the role of iron in these pathways we have recently shown that changes in copper
may contribute to neuronal vulnerability in this disorder.
Language : eng
Ref ID 22
Authors : F. Fang, H. Chen, K. Wirdefeldt, et al.
Title : Infection of the central nervous system, sepsis and amyotrophic lateral sclerosis
Journal : PLoS One 2011 vol.6 part 12 pp e29749
Abstract : BACKGROUND: Severe infections may lead to chronic inflammation in the central nervous system (CNS)
which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless
progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS
patients. METHODOLOGY AND PRINCIPAL FINDINGS: The present study included 4,004 ALS patients identified
from the Swedish Patient Register during 1991-2007 and 20,020 age and sex matched general population
controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous
hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of
hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95%
confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk.
However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after
diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that acute and severe infections unlikely contribute to the
development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free
individuals.
Language : eng
Ref ID 23
Authors : F. Fecto and T. Siddique.
Title : SIGMAR1 mutations, genetic heterogeneity at the chromosome 9p locus, and the expanding etiological
diversity of amyotrophic lateral sclerosis
Journal : Ann.Neurol. 2011 vol.70 part 6 pp 867-870 Language : eng
Ref ID 24
Authors : L. Ferraro, W. T. O'Connor, S. Beggiato, et al.
Title : Striatal NTS(1) , dopamine D(2) and NMDA receptor regulation of pallidal GABA and glutamate release - a
dual-probe microdialysis study in the intranigral 6-hydroxydopamine unilaterally lesioned rat
Journal : Eur.J.Neurosci. 2011
Abstract : The current microdialysis study elucidates a functional interaction between the striatal neurotensin
NTS(1) receptor and the striatal dopamine D(2) and N-methyl-d-aspartic acid (NMDA) receptors in the regulation
of striatopallidal gamma-aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus
GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate
levels. The 6-hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the
decrease in pallidal GABA and glutamate levels induced by the dopamine D(2) -like receptor agonist quinpirole (10
mum). A more pronounced increase in the intrastriatal NMDA- (10 mum) induced increase in pallidal GABA levels
was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the
increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced
increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the
NTS(1) antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine
D(2) and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups.
These actions are modulated by NT via antagonistic NTS(1) /D(2) and facilitatory NTS(1) /NMDA receptor-receptor
interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor
inhibition, effects which all are counteracted by SR48692. Thus, NTS(1) antagonists in combination with
conventional treatments may provide a novel therapeutic strategy in Parkinson's disease.
Language : ENG
Ref ID 25
Authors : C. V. Fontanilla, X. Wei, L. Zhao, et al.
Title : Caffeic acid phenethyl ester extends survival of a mouse model of amyotrophic lateral sclerosis
Journal : Neuroscience 2011
Abstract : There is currently very limited effective pharmacological treatment for amyotrophic lateral sclerosis.
Recent evidence suggests that caffeic acid phenethyl ester has strong anti-inflammatory, anti-oxidative, and antineuronal death properties; thus, the present study tested the effects of caffeic acid phenethyl ester in mice
expressing a mutant superoxide dismutase (SOD1(G93A)) linked to human amyotrophic lateral sclerosis.
Administration of caffeic acid phenethyl ester after symptom onset significantly increased the post-onset survival
and lifespan of SOD1(G93A) mice. Moreover, immunohistochemical analysis detected less activation of microglia
and astrocytes and higher motor neuron counts at an early symptomatic stage (7 days following onset) in the
spinal cords of SOD1(G93A) mice given caffeic acid phenethyl ester treatment. Additionally, lower levels of
phosphorylated p38, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death,
were observed in the spinal cords of SOD1(G93A) mice treated with caffeic acid phenethyl ester for 7 days. These
results indicate that caffeic acid phenethyl ester may represent a novel and effective therapeutic for the treatment
of amyotrophic lateral sclerosis, and these significant neuroprotective effects observed in a commonly used
amyotrophic lateral sclerosis mouse model validate the therapeutic potential of caffeic acid phenethyl ester for
slowing disease progression by attenuating the neuroinflammation and motor neuron cell death associated with
clinical amyotrophic lateral sclerosis pathology.
Language : ENG
Ref ID 26
Authors : P. Gallina, M. Paganini, L. Lombardini, et al.
Title : Progress in restorative neurosurgery: human fetal striatal transplantation in Huntington's disease. Reviews
Journal : J.Neurosurg.Sci. 2011 vol.55 part 4 pp 371-381
Abstract : The purpose of this paper was to offer a review of the rationale, methods, biological and clinical results
of human fetal striatal transplantation (HFST) in the treatment of Huntington's disease (HD). HD is a heritable
neurodegenerative disease in which degeneration of neurons in the striatum leads to motor, psychiatric and
cognitive deficits. The disease is progressive and inexorably lethal. At present there are no curative treatments for
HD. A restorative therapy based on the intrastriatal transplantation of striatal neuroblasts taken from human fetus
is currently being explored as potential treatment in selected HD patients. Pilot clinical trials of HFST have been
started in few neurosurgery restorative centres. Results demonstrated that HFST is feasible and safe without
relevant adverse effects; grafted neuroblasts survive, grow without evidence of neoplasia or teratoma, build new
tissue with striatal-like imaging features, and move into the host brain towards short and long-distance cortical
and sub-cortical targets. HFST delays disease progression and provides a period of improvement and stability.
Even though larger-scale studies are still necessary to establish the true value of such a treatment, at this time,
HFST represents a promising experimental therapy for patients with HD and one of the most interesting clinical
application of restorative neurosurgery.
Language : eng
Ref ID 27
Authors : N. Garcia-Lax, L. Tomas-Roca and F. Marin.
Title : Developmental Expression Pattern of Hspb8 mRNA in the Mouse Brain: Analysis Through Online Databases
Journal : Anat.Rec.(Hoboken) 2011
Abstract : Hspb8 is a member of the Hspb family of chaperone-like proteins. It is involved in several neural
disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, hereditary distal motor neuropathy, and
Charcot-Marie-Tooth's disease. In this work, we aimed to characterize its expression pattern in the mouse brain,
by using the information available at online databases of high-throughput in situ hybridization. Therefore, we
downloaded and analyzed the image series from these databases showing Hspb8 mRNA expression from
embryonic to adult and aging stages. In early gestational embryos, Hspb8 was expressed in the hippocampal
anlagen and in the ventricular layer of rhombomere 4. At perinatal stages, there appeared transitory expression in
the dentate gyrus and the cerebellar cortex. From perinatal to aging stages, the neurons of the mesencephalic
trigeminal nucleus and cranial motor nuclei displayed stable and strong Hspb8 expression. Additionally, along
these stages there was moderate and relatively homogenous expression in the anterodorsal thalamic, lateral
mammillary, arcuate hypothalamic and medial habenular nuclei, and in the locus coeruleus. In its turn, the basal
ganglia, cerebellar inner granular layer and diverse sensory and reticular formation nuclei of the hindbrain
contained scattered cells with strong expression. In conclusion, Hspb8 mRNA is constitutively expressed in specific
brain structures across ontogeny, so that eventually they could be affected by the malfunction or deregulation of
this molecule. Anat Rec,, 2011. (c) 2011 Wiley Periodicals, Inc.
Language : ENG
Ref ID 28
Authors : N. R. Goldberg, V. Fields, L. Pflibsen, M. F. Salvatore and C. K. Meshul.
Title : Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease
Journal : Neurobiol.Dis. 2011
Abstract : Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether
social interaction or novel physical stimulation is responsible for this recovery is controversial. In the current
study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice.
After mice were lesioned using a progressively increased dose (4mg/kg, 8mg/kg, 16mg/kg and 32mg/kg; each
dose daily for 5days), the MPTP-induced behavioral deficits, after the 32mg/kg dose, were reversed with acute lDOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an
appropriate murine model of PD. Mice were housed four per cage for the first 2weeks of progressive lesioning or
vehicle treatment. After the 8mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in
rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in
mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc)
neurons/section, and a 50% decrease in the optical density of TH-ir dorsolateral caudate putamen (CPu) terminals
compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve
(SocE) mice per cage during continued MPTP lesioning for the next 2weeks at 16mg/kg and 32mg/kg MPTP. MPTP
treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing
behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases
in the mean number of TH-ir SNpc neurons/section and CPu TH-ir terminals. CPu TH and dopamine transporter
(DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared
to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute l-DOPA
following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels,
although FF/BB was not significantly different from pre-intervention levels. The reversal from pre-intervention
rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section
and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention
levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but
rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE
mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data
suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at
slowing or blocking further nigrostriatal degeneration.
Language : ENG
Ref ID 29
Authors : P. Gong, J. Roseman, C. G. Fernandez, et al.
Title : Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for
coordinated movement in mice
Journal : Mol.Neurodegener 2011 vol.6 part 1 pp 87
Abstract : ABSTRACT: BACKGROUND: p23 belongs to the highly conserved p24 family of type I transmembrane
proteins, which participate in bidirectional protein transport between the endoplasmic reticulum and Golgi
apparatus. Mammalian p23 has been shown to interact with gamma-secretase complex, and modulate secretory
trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative
modulation of beta-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in
neurons might mitigate cerebral amyloid burden. RESULTS: We generated several lines of transgenic mice
expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in
p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological
problems characterized by tremors and seizure, ataxia, and uncoordinated movements, and premature death. The
severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While
the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain,
abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in
brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation
of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice. CONCLUSIONS: These results
demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by
overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other
neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice
highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously
described negative modulator of gamma-secretase activity and beta-amyloid production. Moreover, our report has
broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent
vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.
Language : ENG
Ref ID 30
Authors : V. Govoni, E. Cesnik, I. Casetta, V. Tugnoli, M. R. Tola and E. Granieri.
Title : Temporal trend of amyotrophic lateral sclerosis incidence in southern Europe: a population study in the
health district of Ferrara, Italy
Journal : J.Neurol. 2012
Abstract : Data about the temporal trend of amyotrophic lateral sclerosis (ALS) incidence in southern Europe are
scarce. Incidence studies on ALS have been carried out in the health district of Ferrara, Italy, since 1960s. We
expanded the previous studies from 1964 to 2009. The study was prospective with a subsequent retrospective
intensive survey of multiple sources of case ascertainment. All patients with a definite and probable ALS according
to the original El Escorial criteria were selected. There were 130 incident cases in the years 1964-2009 giving an
average annual crude incidence of 1.82 per 100,000 population (95% CI 1.53-2.17). An incidence increase during
the study period was estimated in women (chi(2) test for trend = 7.19, p < 0.01) and in the elderly (chi(2) test
for trend = 7.803, p < 0.01). The age-adjusted incidence was stable over time in both women (1.19 per 100,000,
95% CI 0.90-1.52) and men (1.45 per 100,000, 95% CI 0.12-1.84). The annual number of new ALS cases in the
study population followed the Poisson distribution in both sexes as well as in the elderly group of the population.
The present findings suggest that ALS incidence is nearly stable over time. The crude incidence increase we
estimated over time among women is mainly explained by population ageing. The increasing incidence in the
elderly population was likely the consequence of an increasing precision in ALS diagnosis in the elderly since the
increasing attention and care over time of neurologic elderly patients that likely concern elderly women more than
previous time periods rather than better case ascertainment of diagnosed patients. The present findings do not
support the role of specific environmental factors in ALS pathogenesis.
Language : ENG
Ref ID 31
Authors : W. Grisold and A. Vass.
Title : Neuromuscular complications
Journal : Handb.Clin.Neurol. 2012 vol.105 pp 781-803
Abstract : Neuromuscular complications are common in patients with cancer. Their occurrence depends on several
factors, such as the type of malignancy, tumor type, time course of the malignancy, and different types of
treatment, such as surgery, radiotherapy, chemotherapy, or combinations of these. Miscellaneous other
conditions, such as metabolic, paraneoplastic, and infectious causes of neuromuscular dysfunction, occur. In
addition, tumor cachexia is important, with loss of muscle mass a frequent sign in cancer. The peripheral nervous
system consists of cranial nerves, nerve roots, the nerve plexus, peripheral nerves (either as focal
mononeuropathies or polyneuropathies), neuromuscular transmission, and muscle. Conventionally, motor neuron
disease and variants are also considered in this context. The distribution of symptoms and signs varies. Focal and
asymmetrical symptoms and signs point to a focal lesion, which may be caused by the tumor or its metastases,
and also by treatment such as surgery or radiotherapy. The most common distribution is bilateral and
symmetrical, as in neuropathies and myopathies, and most neuromuscular transmission disorders. Pain is often
caused by lesions of the neuromuscular system, and can be a localizing sign; pain strategies against neuropathic
pain are needed. The neurologist seeing patients with neuromuscular symptoms in a neuro-oncological setting has
several roles: the precise localization of the focal lesion of the peripheral nervous system, the extent of tumor
burden on the peripheral nervous system, and, sometimes, the initial detection of a tumor in paraneoplastic
syndromes. If patients develop symptoms during treatment, estimation of the extent of neurotoxicity, which can
be a dose-limiting factor for chemotherapy and also some biological medications, is an issue. Cranial nerve
symptoms and signs, occurring either alone or multiple, are frequent in oncology patients. Peripheral nerve lesions
occur at several sites inside the skull, at their exit from the skull, and in the neck or thorax region. Nerve roots are
frequently affected in patients with cancer. In the majority, this is due to vertebral column metastasis, less often
by meningeal involvement. The cervical and brachial plexi are the sites of local metastasis or infiltration from
adjacent tumors such as lung cancer, breast cancer, or lymphoma. Local recurrence of tumors, less frequently
sequelae of radiotherapy, can cause dysfunction of the sacral plexus, whereas the lumbar plexus is less frequently
involved. Individual peripheral nerves can be damaged at several sites. The most frequent type of lesion is therapy
related (surgery, pressure, malpositioning); neoplastic, toxic, and other causes are rare. Several types of
polyneuropathy exist: paraneoplastic neuropathies can appear before the onset of cancer or may lead to the
detection of cancer. The most frequent types of neuropathy in patients with cancer are chemotherapy-induced
neuropathies, which may be a dose-limiting factor for treatment. Other causes of neuropathy, such as metabolic
derangements, infections, or direct neoplastic involvements, are infrequent. Myasthenia gravis can be considered
to be a paraneoplastic syndrome for thymoma only. Lambert-Eaton myasthenic syndrome is a presynaptic disorder
affecting the cholinergic motor and autonomic synapses. About half of the cases are paraneoplastic, most
frequently associated with small-cell lung cancer. Myopathies occur at various stages of tumor disease. They may
be the presenting sign of a tumor disease like inflammatory myopathies, such as dermatomyositis or polymyositis,
or appear during tumor treatment, such as metabolic or toxic myopathy, or in the late stages of cancer, such as
cachexia. In clinical practice, direct involvement of the peripheral nervous system by cancer is as important as
systemic effects on the peripheral nerve structures. For some conditions, such as tumor cachexia, neuropathies in
advanced cancer, or in terminally ill patients, similar mechanisms can be suspected, which also occur in severe
systemic non-neoplastic diseases such as chronic infections; a common pathway of pathogenesis can be
suspected.
Language : eng
Ref ID 32
Authors : H. Harris and D. C. Rubinsztein.
Title : Control of autophagy as a therapy for neurodegenerative disease
Journal : Nat.Rev.Neurol. 2011
Abstract : Autophagy is an intracellular degradation process that clears long-lived proteins and organelles from the
cytoplasm. It involves the formation of double-membraned structures called autophagosomes that can engulf
portions of cytoplasm containing oligomeric protein complexes and organelles, such as mitochondria.
Autophagosomes fuse with lysosomes and their contents then are degraded. Failure of autophagy in neurons can
result in the accumulation of aggregate-prone proteins and neurodegeneration. Pharmacological induction of
autophagy can enhance the clearance of intracytoplasmic aggregate-prone proteins, such as mutant forms of
huntingtin, and ameliorate pathology in cell and animal models of neurodegenerative diseases. In this Review, the
autophagic machinery and the signaling pathways that regulate the induction of autophagy are described. The
ways in which dysfunctions at multiple stages in the autophagic pathways contribute to numerous neurological
disorders are highlighted through the use of examples of Mendelian and complex conditions, including Alzheimer
disease, Parkinson disease and forms of motor neuron disease. The different ways in which autophagic pathways
might be manipulated for the therapeutic benefit of patients with neurodegenerative disorders are also considered.
Language : ENG
Ref ID 33
Authors : T. Hideyama, T. Yamashita, H. Aizawa, et al.
Title : Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons
Journal : Neurobiol.Dis. 2011
Abstract : Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In
spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA
2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons
expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore,
investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons
of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R
site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and
disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family
(ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only
edited GluA2 mRNA. Q/R site-unedited GluA2 mRNA was expressed in a significant proportion of motor neurons
from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects
expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the
motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those
expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound
pathological change relevant to death of motor neurons in ALS.
Language : ENG
Ref ID 34
Authors : Y. Y. Hsu, Y. J. Jong, H. H. Tsai, Y. T. Tseng, L. M. An and Y. C. Lo.
Title : Triptolide increases SMN transcript and protein levels in human SMA fibroblasts and improves survival in
SMA-like mice
Journal : Br.J.Pharmacol. 2012
Abstract : Background and purpose: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since
disease severity is related to the amount of survival motor neuron (SMN) protein, up-regulated functional SMN
protein levels from the SMN2 gene is considered a major SMA drug-discovery strategy. In this study, we explore
triptolide, a diterpene triepoxide purified from Tripterygium wilfordiiHook. F., as a new target increasing SMN
protein. Experimental approach: The effects and mechanisms of triptolide on the production of SMA protein were
determined by cell-based assays using motor neuronal cell line NSC34 and skin fibroblasts from SMA patients.
Wild-type (Smn(+/+) SMN2(-/-) , C57BL/6) and SMA-like (Smn(-/- ) SMN2) mice received triptolide (0.01 or 0.1
mg kg(-1) day(-1) ) by intraperitoneal injection to examine the survival rate and the level of change in SMN
protein in neurons and muscle tissue. Key results: In NSC34 cells and human SMA fibroblasts, triptolide at
picromolar concentration significantly increased SMN protein expression and SMN complex component (Gemin2
and Gemin3) amounts. In human SMA fibroblasts, triptolide increased SMN-containing nuclear gems and the ratio
of full length transcripts (FL-SMN2) to transcripts lacking exon 7 (SMN2Delta7). Furthermore, in SMA-like mice,
triptolide significantly increased SMN protein levels of brain, spinal cord and gastrocnemius muscle. Furthermore,
triptolide treatment increased survival and reduced weight loss in SMA-like mice. Conclusions and implications:
Triptolide enhances SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing
nuclear gems, and extends survival in SMA mice, which suggests triptolide might be a potential target for SMA
therapy.
Language : ENG
Ref ID 35
Authors : J. Hu, K. Chen, B. Ni, L. Li, G. Chen and S. Shi.
Title : A novel SOD1 mutation in amyotrophic lateral sclerosis with a distinct clinical phenotype
Journal : Amyotroph Lateral Scler. 2012 vol.13 part 1 pp 149-154
Abstract : Abstract Familial amyotrophic lateral sclerosis (FALS) accounts for about 5% of cases of the
neurodegenerative disorder ALS. At least 100 Cu/Zn superoxide dismutase (SOD1) genetic mutations have been
associated with FALS. We identified a FALS family in China with an atypical clinical phenotype. To investigate the
SOD1 gene mutations in this family, five exons of the SOD1 gene from each living patient were amplified by PCR
and screened by SSCP and direct DNA sequencing. SSCP analysis demonstrated a mutation in exon 2 of SOD1,
and DNA sequencing demonstrated the presence of an insertion mutation in exon 2 that has not been reported
previously. The mutant SOD1 gene encodes a truncated protein of 35 amino acid residues compared to the normal
SOD1 protein of 153 amino acids. In conclusion, The SOD1 exon 2 mutation is likely to be the etiological factor of
ALS in this family.
Language : eng
Ref ID 36
Authors : Y. Iguchi, M. Katsuno, S. Takagi, et al.
Title : Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to
TDP-43 proteinopathies
Journal : Neurobiol.Dis. 2011
Abstract : TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive inclusion of TDP-43
proteinopathies including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated
inclusions, which is now referred to as FTLD-TDP. TDP-43 in the aberrant inclusion is known to be
hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re-distribute from
nucleus to cytoplasm or neurite. The pathogenic role of these modifications, however, has not been clarified.
Furthermore, there is no evidence about the initial cause of these modifications. Herein we show that ethacrynic
acid (EA), which is able to increase cellular oxidative stress through glutathione depletion, induces TDP-43 Cterminal phosphorylation at serine 403/404 and 409/410, insolubilization, C-terminal fragmentation, and
cytoplasmic distribution in NSC34 cells and primary cortical neurons. In the investigation using a
nonphosphorylable mutant of TDP-43, there was no evidence that C-terminal phosphorylation of TDP-43
contributes to its solubility or distribution under EA induction. Our findings suggest that oxidative stress induced
by glutathione depletion is associated with the process of the pathological TDP-43 modifications and provide new
insight for TDP-43 proteinopathies.
Language : ENG
Ref ID 37
Authors : V. Jackson-Lewis, J. Blesa and S. Przedborski.
Title : Animal models of Parkinson's disease
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S183-5
Abstract : Parkinson's disease (PD) is a disease of an aging population and its etiology is still unknown. In vivo
models are attempts to capture as many of the hallmarks of PD as possible. To this end, a number of animal
models are in use. These models parallel our thinking about the etiology of PD. Thus, herein, we discuss the most
popular neurotoxin animal models, 6-hydroxydopamine and MPTP as one school of thought believes that PD is the
result of a toxic insult. Since several researchers think that pesticide and herbicide use can increase the risk of
developing PD, we review some of the aspects of rotenone and paraquat in rodents. Furthermore, now that we
know that 10% of all PD cases are genetic in nature, we discuss some of the more common genetic rodent models
of PD. None of the above models captures all of the hallmarks of PD. Thus, a given model should never be used
indiscriminately to investigate every question, but should instead be carefully selected on the basis of being the
most suitable model for the question being asked.
Language : eng
Ref ID 38
Authors : S. K. Jankelowitz and D. Burke.
Title : Do the motor manifestations of parkinson disease alter motor axon excitability?
Journal : Muscle Nerve 2012 vol.45 part 1 pp 43-47
Abstract : Background: Axonal excitability is altered in common medical conditions such as stroke, multiple
sclerosis, and spinal cord injury. Given the motor neuron changes in the presence of rigidity and tremor in
Parkinson disease, we examine whether there are also changes in motor axon excitability. Methods: Axonal
excitability studies were performed in 15 Parkinson subjects and 12 age-matched control subjects. Results: There
was no significant difference in excitability indices between Parkinson subjects and control subjects. Conclusions:
It is unlikely that the lack of change in the excitability indices reflects a balance between the effects of
bradykinesia ("underactivity") and the effects of rigidity and tremor ("overactivity") on the motoneuron and its
axon. It is more likely that plastic changes in motoneuron properties do not occur symmetrically with decreases
and increases in activity, being more profound when activity levels are interrupted and less obvious when they are
enhanced. Muscle Nerve 45: 43-47, 2012.
Language : eng
Ref ID 39
Authors : M. L. Janssen, D. G. Zwartjes, S. K. Tan, et al.
Title : Mild dopaminergic lesions are accompanied by robust changes in subthalamic nucleus activity
Journal : Neurosci.Lett. 2011
Abstract : The subthalamic nucleus (STN) is a major player in the input and output of the basal ganglia motor
circuitry. The neuronal regular firing pattern of the STN changes into a pathological bursting mode in both
advanced Parkinson's disease (PD) and in PD animals models with severe dopamine depletion. One of the current
hypothesis, based on clinical and experimental evidence, is that this typical burst activity is responsible for some
of the principal motor symptoms. In the current study we tested whether mild DA depletion, mimicking early
stages of PD, induced deficits in motor behaviour and changes in STN neuronal activity. The present study
demonstrated that rats with a mild lesion (20-40% loss of DA neurons) and a slowed motor response, but without
gross motor abnormalities already have an increased number of bursty STN neurons under urethane anaesthesia.
These findings indicate that the early increase in STN burst activity is a compensatory mechanism to maintain the
dopamine homeostasis in the basal ganglia.
Language : ENG
Ref ID 40
Authors : S. Jurici, A. Laquerriere, A. L. Bedat-Millet, et al.
Title : An Autopsy Case of Amyotrophic Lateral Sclerosis with Waldenstrom Macroglobulinemia and Anti-MAG
Gammopathy
Journal : Case Rep.Neurol. 2011 vol.3 part 3 pp 294-300
Abstract : We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis
(ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated
glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been
reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link
between anti-MAG antibodies and ALS.
Language : eng
Ref ID 41
Authors : I. Kacem, B. Funalot, F. Torny, G. Lautrette, P. M. Andersen and P. Couratier.
Title : Early onset Parkinsonism associated with an intronic SOD1 mutation
Journal : Amyotroph Lateral Scler. 2012
Abstract : We report on a patient belonging to a large family with autosomal-dominant amyotrophic lateral
sclerosis, who developed asymmetrical akineto-rigid symptoms at 33 years of age. He had no signs of lower motor
neuron disease after four years of follow-up. All seven ALS patients from this family harboured a mutation located
in the fourth intron of the SOD1 gene. The proband also harboured the same mutation, associated with a 40%
decrease in SOD1 erythrocyte activity. This case report suggests that SOD1 mutations might be associated with
marked phenotypic variability (ALS or early onset Parkinsonism in this family).
Language : ENG
Ref ID 42
Authors : R. Kaji, Y. Izumi, Y. Adachi and S. Kuzuhara.
Title : ALS-Parkinsonism-Dementia complex of Kii and other related diseases in Japan
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S190-1
Abstract : The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic
expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological
manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many
neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and
1980s. In the 1990s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to
Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced
ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC. We recently found a
new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed
involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also
showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to
be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that
the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or
environmental factors.
Language : eng
Ref ID 43
Authors : R. Kassa, V. Monterroso, J. Wentzell, et al.
Title : Proximal Giant Neurofilamentous Axonopathy in Mice Genetically Engineered to Resist Calpain and Caspase
Cleavage of alpha-II Spectrin
Journal : J.Mol.Neurosci. 2012
Abstract : We use 1,2-diacetylbenzene (1,2-DAB) to probe molecular mechanisms of proximal giant
neurofilamentous axonopathy (PGNA), a pathological hallmark of amyotrophic lateral sclerosis. The spinal cord
proteome of rodents displaying 1,2-DAB PGNA suggests a reduction in the abundance of alpha-II spectrin (Spna2),
a key protein in the maintenance of axonal integrity. Protein immunoblotting indicates that this reduction is due to
Spna2 degradation. We investigated the importance of such degradation in 1,2-DAB PGNA. Spna2 mutant mice
lacking a calpain- and/or caspase-sensitive domain (CSD), thus hypothetically resistant to 1,2-DAB, and wild-type
littermates, were treated with 1,2-DAB, 35 mg/kg/day, or saline control, for 3 weeks. 1,2-DAB induced motor
weakness and PGNA, irrespective of the genotype. Spna2-calpain breakdown products were not detected in
mutant mice, which displayed a normal structure of the nervous system under saline treatment. Intriguingly,
treatment with 1,2-DAB reduced the abundance of the caspase-specific 120-kDa Spna2 breakdown products. Our
findings indicate that degradation of Spna2 by calpain- and/or caspase is not central to the pathogenesis of 1,2DAB axonopathy. In addition, the Spna2-CSD seems to be not required for the maintenance of the cytoskeleton
integrity. Our conceptual framework offers opportunities to study the role of calpain-caspase cross talk, including
that of the protease degradomics, in models of axonal degeneration.
Language : ENG
Ref ID 44
Authors : D. Keckarevic, Z. Stevic, M. Keckarevic-Markovic, M. Kecmanovic and S. Romac.
Title : A novel P66S mutation in exon 3 of the SOD1 gene with early onset and rapid progression
Journal : Amyotroph Lateral Scler. 2012
Abstract : Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in adults of unknown origin in most
cases. Here we report a novel P66S mutation in exon 3 of the SOD1 gene in an apparently sporadic ALS patient
with unusual early onset and rapid disease progression. Our data widen the spectrum of SOD1 mutations and
clinical presentations of ALS.
Language : ENG
Ref ID 45
Authors : Z. Kohl, B. Winner, K. Ubhi, et al.
Title : Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model
Journal : Eur.J.Neurosci. 2012 vol.35 part 1 pp 10-19
Abstract : The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations
is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant
alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in
models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of
depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an
unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic
animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI)
fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG
neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic
fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in
treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is
predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by
induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of
brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study
underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in
alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD.
Language : eng
Ref ID 46
Authors : E. E. Konofagou, Y. S. Tung, J. Choi, T. Deffieux, B. Baseri and F. Vlachos.
Title : Ultrasound-Induced Blood-Brain Barrier Opening
Journal : Curr.Pharm.Biotechnol. 2012
Abstract : Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease;
350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four
diseases account for more than 20 million patients. In addition, aging greatly increases the risk of
neurodegenerative disease. Although great progress has been made in recent years toward understanding of these
diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of
the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny
fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a
significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in
conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and
regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper
is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB
opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in
vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is
assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown
that the BBB can be disrupted safely and transiently under specific acoustic (pressures under 0.45 MPa) and
microbubble (diameter under 8 microm) conditions.
Language : ENG
Ref ID 47
Authors : M. Kurahashi, Y. Nakano, G. W. Hennig, S. M. Ward and K. M. Sanders.
Title : Platelet derived growth factor receptor alpha-positive cells in the tunica muscularis of human colon
Journal : J.Cell.Mol.Med. 2012
Abstract : BACKGROUND AND AIMS: An obstacle to understanding motor pathologies of the GI tract is that the
physiology of some of the cellular components of the gut wall is not understood. Morphologists identified
fibroblast-like cells in the tunica muscularis many years ago, but little is know about these interstitial cells because
of inadequate techniques to identify these cells. Recent findings have shown that fibroblast-like cells express
PDGFRalpha in mice and antibodies for these receptors can be used to label the cells. METHODS: We used
immunohistochemical techniques to study the phenotype and intercellular relationships of fibroblast-like cells in
the human colon. RESULTS: Fibroblast-like cells are labeled specifically with antibodies to PDGFRalpha and widely
distributed through the tunica muscularis of human colon. These cells form discrete networks in the region of the
myenteric plexus and within the circular and longitudinal muscle layers. PDGFRalpha(+) cells are distinct from cKit(+) interstitial cells of Cajal and closely associated with varicose processes of neurons expressing substance P
(excitatory motor neurons) or nNOS (inhibitory motor neurons). PDGFRalpha(+) cells express small conductance
Ca(2+) -activated K(+) channels (SK3), which are likely to mediate purinergic neural regulation of colonic
muscles. CONCLUSIONS: Our data suggest that PDGFRalpha(+) cells may have an important role in transducing
inputs from enteric motor neurons. This study identifies reagents and techniques that will allow investigation of
this class of interstitial cells and help to develop an understanding of the role of PDGFRalpha(+) cells in the human
GI tract in health and disease. (c) 2011 The Authors Journal of Cellular and Molecular Medicine (c) 2011
Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Language : ENG
Ref ID 48
Authors : S. Lacomble, S. Vaughan, M. Deghelt, F. F. Moreira-Leite and K. Gull.
Title : A Trypanosoma brucei Protein Required for Maintenance of the Flagellum Attachment Zone and Flagellar
Pocket ER Domains
Journal : Protist 2011
Abstract : Trypanosomes and Leishmanias are important human parasites whose cellular architecture is centred on
the single flagellum. In trypanosomes, this flagellum is attached to the cell along a complex flagellum attachment
zone (FAZ), comprising flagellar and cytoplasmic components, the integrity of which is required for correct cell
morphogenesis and division. The cytoplasmic FAZ cytoskeleton is conspicuously associated with a sheet of
endoplasmic reticulum termed the 'FAZ ER'. In the present work, 3D electron tomography of bloodstream form
trypanosomes was used to clarify the nature of the FAZ ER. We also identified TbVAP, a T. brucei protein whose
knockdown by RNAi in procyclic form cells leads to a dramatic reduction in the FAZ ER, and in the ER associated
with the flagellar pocket. TbVAP is an orthologue of VAMP-associated proteins (VAPs), integral ER membrane
proteins whose mutation in humans has been linked to familial motor neuron disease. The localisation of tagged
TbVAP and the phenotype of TbVAP RNAi in procyclic form trypanosomes are consistent with a function for TbVAP
in the maintenance of sub-populations of the ER associated with the FAZ and the flagellar pocket. Nevertheless,
depletion of TbVAP did not affect cell viability or cell cycle progression.
Language : ENG
Ref ID 49
Authors : N. Z. Lax, R. G. Whittaker, P. D. Hepplewhite, et al.
Title : Sensory neuronopathy in patients harbouring recessive polymerase gamma mutations
Journal : Brain 2011
Abstract : Defects in the mitochondrial DNA replication enzyme, polymerase gamma, are an important cause of
mitochondrial disease with approximately 25% of all adult diagnoses attributed to mutations in the POLG gene.
Peripheral neuronopathy is often part of the clinical syndrome and can represent the most disabling feature. In
spite of this, the molecular mechanisms underlying the neuronopathy remain to be elucidated and treatment
strategies are limited. In the present study, we use a combined approach comprising clinical, electrophysiological,
neuropathological and molecular genetic investigations to unravel the mechanisms underpinning peripheral
neuronopathy in autosomal recessive polymerase gamma-related disease. Electrophysiological assessments
documented a dorsal root ganglionopathy in all 11 cases. Of the 11 cases, eight also showed changes consistent
with motor fibre loss. Detailed neuropathological investigation of two patients confirmed the electrophysiological
findings, revealing atrophy of posterior columns and striking neuronal cell loss from the dorsal root ganglia, which
was accompanied by severe mitochondrial biochemical abnormalities involving respiratory chain complexes I and
IV due to clonally-expanded mitochondrial DNA deletions and a significant reduction in mitochondrial DNA copy
number in affected neurons. We propose that the respiratory chain defects, secondary to mitochondrial DNA
deletion and depletion, are likely to be responsible for pathology observed in the dorsal root ganglion and the
sensory ganglionopathy documented electrophysiologically.
Language : ENG
Ref ID 50
Authors : J. B. Lee, K. A. Lee, J. M. Hong, G. I. Suh and Y. C. Choi.
Title : Homozygous SMN2 Deletion is a Major Risk Factor among Twenty-Five Korean Sporadic Amyotrophic Lateral
Sclerosis Patients
Journal : Yonsei Med.J. 2012 vol.53 part 1 pp 53-57
Abstract : Purpose: The association between survivor motor neuron (SMN) gene deletion and spinal muscular
atrophy suggests that sporadic amyotrophic lateral sclerosis (sALS) may be related to SMN deletion. We examined
the association between the SMN genotype and susceptibility to and severity of sALS. Materials and Methods: We
genotyped the copy number of SMN1 and SMN2 in 25 patients diagnosed with sporadic ALS and 100 healthy
subjects in a Korean population. Onset age and medical research council (MRC) scale were compared among
patients according to SMN1 : SMN2 genotypes. Results: There was a significantly higher incidence of homozygous
deletion of SMN2 (SMN1 : SMN2 genotype, 2 : 0) in sALS patients (20%) than in the normal controls (2%)
(p<0.001). The onset age for patients with homozygous deletion of SMN2 (2 : 0) was significantly younger (34+/15.38 years) than that of patients with 2 : 1, 2 : 2 and 2 : 3 of the SMN1 : SMN2 genotype (59.5+/-5.09;
52.69+/-16.46 and 50+/-0.00 years) (p=0.049). The ratio of patients with an MRC scale above G4- was smaller in
the 2 : 0 genotype (40%) than in the 2 : 1, 2 : 2 and 2 : 3 genotypes (83.3%, 100% and 100%) (p=0.02).
Conclusion: The homozygous SMN2 deletion (2 : 0) was statistically more frequent and associated with earlier
onset age and lower MRC scale in Korean sALS patients. These suggest that SMN2 deletion may be one of the
factors associated with susceptibility to and severity of sALS in a Korean population.
Language : eng
Ref ID 51
Authors : T. J. Lemoine, K. J. Swoboda, S. L. Bratton, R. Holubkov, M. Mundorff and R. Srivastava.
Title : Spinal muscular atrophy type 1: Are proactive respiratory interventions associated with longer survival?
Journal : Pediatr.Crit.Care.Med. 2012
Abstract : CONTEXT: Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading
genetic cause of death in infancy and early childhood. OBJECTIVE: To determine whether the early initiation of
noninvasive respiratory interventions is associated with longer survival. DESIGN: Single-institution retrospective
cohort study identified children with spinal muscular atrophy type 1 from January 1, 2002 to May 1, 2009 who
were followed for 2.3 mean yrs. SETTING: Tertiary care children's hospital and outpatient clinics in a vertically
integrated healthcare system. PATIENTS OR OTHER PARTICIPANTS: Forty-nine children with spinal muscular
atrophy type 1 were grouped according to the level of respiratory support their caregivers chose within the first 3
months after diagnosis: proactive respiratory care (n = 26) and supportive care (n = 23). INTERVENTIONS:
Proactive respiratory care included bilevel noninvasive ventilation during sleep and twice a day cough assist while
supportive respiratory care included suctioning, with or without supplemental oxygen. MEASUREMENTS AND MAIN
RESULTS: Kaplan-Meier survival curves were assessed based on intention to treat. Children treated with early
proactive respiratory support had statistically longer survival compared to supportive care (log rank 0.047);
however, the adjusted hazard ratio for survival was not statistically different (2.44 [95% confidence interval 0.847.1]). Children in the proactive group were more likely to be hospitalized for respiratory insufficiency (83% vs.
46%) and had shortened time after diagnosis until first hospital admission for respiratory insufficiency (median
118 vs. 979 days). CONCLUSION: Longer survival time with spinal muscular atrophy type 1 is associated with
early, noninvasive respiratory care interventions after diagnosis.
Language : ENG
Ref ID 52
Authors : X. Li, J. Sundquist and K. Sundquist.
Title : Subsequent Risks of Parkinson Disease in Patients with Autoimmune and Related Disorders: A Nationwide
Epidemiological Study from Sweden
Journal : Neurodegener Dis. 2011
Abstract : Objectives: To investigate associations between autoimmune disorders and Parkinson disease (PD), and
to study whether the risk is associated with follow-up time and age. Methods: Standardized incidence ratios (SIRs)
were calculated for PD in patients with autoimmune disorders by comparing them to subjects without autoimmune
disorders. Results: Among 310,522 patients with a total of 33 conditions of autoimmune disorders, 932 patients
developed subsequent PD, giving an overall SIR of 1.33 and 1.19 for PD diagnosed later than 1 year after followup. Six types of autoimmune disorders showed an increased risk. These conditions included: amyotrophic lateral
sclerosis, Graves's disease/hyperthyroidism, Hashimoto's disease/hypothyroidism, multiple sclerosis, pernicious
anemia, and polymyalgia rheumatica. The risks depended on the age at hospitalization for PD. Conclusions: A 33%
overall excess risk of PD was noted among patients with an autoimmune disorder; the risk was increased during
the first 10 years of follow-up after hospitalization of autoimmune disorders.
Language : ENG
Ref ID 53
Authors : S. Liang, D. Christner, S. Du Laux and D. Laurent.
Title : Significant neurological improvement in two patients with amyotrophic lateral sclerosis after 4 weeks of
treatment with acupuncture injection point therapy using enercel
Journal : J.Acupunct.Meridian Stud. 2011 vol.4 part 4 pp 257-261
Abstract : Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly fatal, degenerative disorder of the upper
motor neurons that does not currently have an effective treatment regimen. Here, we report two patients with ALS
who were treated with 4 weeks of acupuncture injection point therapy using Enercel. These patients were
administered 0.25-0.5cc Enercel Plus IM to specific acupuncture points for 5 days per week for 4 weeks. Patient
#1 presented with flaccid paralysis of all four extremities and impaired speech and swallowing. By Week 4, she
demonstrated significant improvement in her motor strength in all four extremities (R>L) and improved speech
and swallowing. However, she did not continue to receive the Enercel acupoint injections, and she subsequently
demonstrated a slow, progressive loss of neurological function during the ensuing 3 months, as shown on followup examinations. Patient #2 had significantly impaired speech and mild motor loss in the upper extremities and
the left leg. After 4 weeks of treatment, his voice had significantly improved to the point where his speech was
understandable and his motor functions had returned to normal. He continued receiving Enercel acupoint
injections during the 3-month follow-up period and his clinical improvements were maintained. Thus, these two
patients with ALS showed clinical improvements after 4 weeks of Enercel acupoint injection therapy. Follow-up
data suggests that ongoing therapy may be necessary in order to maintain these positive effects. This preliminary
study merits further study and confirmation.
Language : eng
Ref ID 54
Authors : P. Lillo, S. Savage, E. Mioshi, M. C. Kiernan and J. R. Hodges.
Title : Amyotrophic lateral sclerosis and frontotemporal dementia: A behavioural and cognitive continuum
Journal : Amyotroph Lateral Scler. 2012 vol.13 part 1 pp 102-109
Abstract : Abstract Our objective was to compare the cognitive and behavioural profile of patients with
amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD), and to explore the
continuum between these disorders according to neuropsychological and behavioural performance using novel
methods of testing and analysis. Twenty patients with ALS, 20 bvFTD patients and 20 healthy controls completed
a neuropsychiatric and neuropsychological assessment including cognitive screening, working memory, inhibitory
control, decision making and emotion recognition. The resulting neuropsychological and behavioural data were
analysed by Rasch analysis. ALS patients showed a similar profile to bvFTD patients on tests of working memory,
inhibitory control and behavioural measures. Nine ALS patients (45%) had cognitive impairment and five (25%)
met criteria for bvFTD. Even in a subset of MND patients with no impairment on the ACE-R, subtle impairment of
inhibitory control together with moderate to severe apathy, were found. The Rasch analysis confirmed that all
patients could be ranked on the same continuum, based on their neuropsychological performance and behaviour.
Thus, the cognitive and behavioural profiles of ALS mirror those seen in bvFTD. Impaired inhibitory control and
behavioural changes suggest subtle orbitofrontal dysfunction in ALS. The Rasch analysis revealed a clear overlap
between bvFTD and ALS.
Language : eng
Ref ID 55
Authors : D. Lo Coco and V. La Bella.
Title : Fatigue, sleep, and nocturnal complaints in patients with amyotrophic lateral sclerosis
Journal : Eur.J.Neurol. 2012
Abstract : Background and purpose: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS).
Although sleep disturbances are a candidate factor that may interfere with fatigue in patients with ALS, the role of
sleep-related abnormalities in determining fatigue in ALS is unknown. Objective: To evaluate the frequency and
determinants of fatigue in a group of 91 consecutive patients with ALS, with special attention to the relationship
between fatigue and sleep problems. Methods: Measures included the Fatigue Severity Scale (FSS), Pittsburgh
Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating Scale-Revised (ALSFRS-R),
and Beck Depression Inventory (BDI). Results: The mean FSS score was 4.35 +/- 1.1, and 48 patients with ALS
(52.75%) reported clinical significant fatigue. FSS score correlated with ALSFRS-R score, forced vital capacity,
ESS, BDI, and global PSQI score. Patients with fatigue were significantly more disabled and more frequently
reported difficulties staying asleep and nocturnal complaints, such as nocturia and disturbing muscle cramps. After
multivariate analysis, patients' disability and nocturnal complaints were significantly associated with fatigue.
Conclusion: In this study, we demonstrated that fatigue, a troublesome and disabling symptom in ALS, is
associated with physical impairment and night-time complaints (such as nocturia and muscle cramps), suggesting
that treating sleep problems might be useful in alleviating fatigue in these patients.
Language : ENG
Ref ID 56
Authors : M. Luigetti, A. Conte, A. Del Grande, G. Bisogni, A. Romano and M. Sabatelli.
Title : Sural nerve pathology in ALS patients: a single-centre experience
Journal : Neurol.Sci. 2011
Abstract : Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor
neurons. Sensory involvement is thought not to be a feature of ALS. We reviewed 17 cases of sural nerve biopsies
performed in a large cohort of ALS patients referred to our centre over a 23-year period. More than two-third of
biopsies revealed a variable degree of axonal loss. In one case, pathological findings suggested the concomitant
presence of an inherited neuropathy, subsequently confirmed by genetic evaluation. In another case, pathological
and neurographic data were similar to those of an inflammatory demyelinating neuropathy, but the clinical course
corroborated the diagnosis of ALS. Our data confirm that sensory nerve involvement may be found in ALS
patients. This finding should prompt physicians to carefully investigate a possible alternative diagnosis, but does
not exclude the possibility that the patient may have ALS.
Language : ENG
Ref ID 57
Authors : J. Magrane, M. A. Sahawneh, S. Przedborski, A. G. Estevez and G. Manfredi.
Title : Mitochondrial Dynamics and Bioenergetic Dysfunction Is Associated with Synaptic Alterations in Mutant
SOD1 Motor Neurons
Journal : J.Neurosci. 2012 vol.32 part 1 pp 229-242
Abstract : Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a
rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which
mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise.
Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to
localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in
neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired
mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live
imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing
mutant or wild-type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial
fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with
reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller
mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential.
Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal
synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron
mitochondria, since they are absent in wild-type SOD1 motor neurons, they do not involve other organelles, and
they are not found in cortical neurons. Together, these results suggest that impaired mitochondrial dynamics may
contribute to the selective degeneration of motor neurons in SOD1-FALS.
Language : eng
Ref ID 58
Authors : S. A. Mandel, T. Fishman-Jacob and M. B. Youdim.
Title : Genetic reduction of the E3 ubiquitin ligase element, SKP1A and environmental manipulation to emulate
cardinal features of Parkinson's disease
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S177-9
Abstract : AIMS: To assess whether reduction of Skp1 will increase the vulnerability of dopaminergic neurons to
genetic/environmental factors known to play a role in the pathological process of PD. METHODS: Short hairpin
RNA lentiviruses infection of substantia nigra (SN)-derived cell-line (SN4741) and mice intranigral injection.
RESULTS: We have knocked down the expression of SKP1A, an E3 ubiquitin ligase element, found significantly
decreased in human SN in patients with PD. The deficiency of SKP1A in SN4741 cells closely recapitulated cardinal
features of the dopamine (DA) neuron pathology of human PD, such as decreased expression of DA phenotypic
markers and cell cycle aberrations. Moreover, the knocked down cells displayed a lethal phenotype in
differentiated cells exhibiting proteinaceous round inclusions, which were almost identical in composition to human
Lewy bodies. Knock down of SKP1A rendered SN4741 cells especially sensitive to genetic reduction of the DA
metabolizing enzyme, aldehyde dehydrogenase 1 and exposure to external Stressors implicated in PD pathology.
CONCLUSION: Future studies should contemplate intrinsic and environmental manipulations in Skp1-deficient
animals to emulate the motor and non-motor disabilities, the progressive nature of PD, and striatal-nigral and
adjacent areas pathology. This model may provide a reliable "platform" to develop new therapeutic interventions
for PD.
Language : eng
Ref ID 59
Authors : I. Marcilio, N. Gouveia, M. L. Pereira Filho and L. Kheifets.
Title : Adult mortality from leukemia, brain cancer, amyotrophic lateral sclerosis and magnetic fields from power
lines: a case-control study in Brazil
Journal : Rev.Bras.Epidemiol. 2011 vol.14 part 4 pp 580-588
Abstract : Recent publications renewed interest in assessing potential health risks for subjects living close to
transmission lines. This study aimed at evaluating the association of both distance of home address to the nearest
overhead transmission line and of the calculated magnetic fields from the power lines and mortality from
leukemia, brain cancer, and amyotrophic lateral sclerosis. We carried out a death certificate based case-control
study accessing adult mortality in the Metropolitan Region of Sao Paulo, in Brazil. Analysis included 1,857 cases of
leukemia, 2,357 of brain cancer, 367 of amyotrophic lateral sclerosis, and 4,706 as controls. An increased risk for
mortality from leukemia among adults living at closer distances to transmission lines compared to those living
further then 400 m was found. Risk was higher for subjects that lived within 50 m from power lines (OR=1.47;
95% CI=0.99-2.18). Similarly, a small increase in leukemia mortality was observed among adults living in houses
with higher calculated magnetic fields (OR=1.61; 95% CI=0.91-2.86 for those exposed to magnetic fields >0.3
microT). No increase was seen for brain tumours or amyotrophic lateral sclerosis. Our findings are suggestive of a
higher risk for leukemia among subjects living closer to transmission lines, and for those living at homes with
higher calculated magnetic fields, although the risk was limited to lower voltage lines.
Language : eng
Ref ID 60
Authors : J. A. Markowitz, P. Singh and B. T. Darras.
Title : Spinal muscular atrophy: a clinical and research update
Journal : Pediatr.Neurol. 2012 vol.46 part 1 pp 1-12
Abstract : Spinal muscular atrophy, a hereditary degenerative disorder of lower motor neurons associated with
progressive muscle weakness and atrophy, is the most common genetic cause of infant mortality. It is caused by
decreased levels of the "survival of motor neuron" (SMN) protein. Its inheritance pattern is autosomal recessive,
resulting from mutations involving the SMN1 gene on chromosome 5q13. However, unlike many other autosomal
recessive diseases, the SMN gene involves a unique structure (an inverted duplication) that presents potential
therapeutic targets. Although no effective treatment for spinal muscular atrophy exists, the field of translational
research in spinal muscular atrophy is active, and clinical trials are ongoing. Advances in the multidisciplinary
supportive care of children with spinal muscular atrophy also offer hope for improved life expectancy and quality of
life.
Language : eng
Ref ID 61
Authors : C. M. Matullo, K. J. O'Regan, M. Curtis and G. F. Rall.
Title : CNS Recruitment of CD8+ T Lymphocytes Specific for a Peripheral Virus Infection Triggers
Neuropathogenesis during Polymicrobial Challenge
Journal : PLoS Pathog. 2011 vol.7 part 12 pp e1002462
Abstract : Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology,
including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such
diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the
tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test
this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral
infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with
both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV).
While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice,
with approximately 50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of
CD8(+) T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial
proportion (>35%) of these infiltrating CD8(+) lymphocytes were LCMV-specific, despite no detectable LCMV in
CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforinindependent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV.
These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that
CD8(+) T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By
extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular
agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma
can render the CNS susceptible to pathogen-independent immune attack.
Language : eng
Ref ID 62
Authors : F. Mazanderani, L. Locock and J. Powell.
Title : Being differently the same: The mediation of identity tensions in the sharing of illness experiences
Journal : Soc.Sci.Med. 2011
Abstract : The sharing of experiences between patients has become increasingly privileged as a source of
knowledge and support in contemporary healthcare. Despite this, relatively little is known about the processes
whereby people's experiences become, or fail to become, valued as sources of health-related knowledge in
different contexts. Through a secondary analysis of 87 interviews conducted between 2006 and 2008 in the UK
with people affected by motor neurone disease (46 interviews) and Parkinson's disease (41 interviews), we
explore the identity work involved in turning other people's experiences into 'experiential knowledge' that can be
shared between patients. Of particular interest is how the turning of others' experiences into knowledge is
presupposed by negotiating a particular type of identity tension - what, drawing on the work of Paul Ricoeur
(2003) on metaphor, we refer to as 'being differently the same'. We examine the way in which people living with
motor neurone disease and Parkinson's disease spoke of managing this tension as part of the process of accessing
and valuing other patients' experiences, both epistemologically and emotionally. Instead of treating others'
experiences as a pre-given source of knowledge, we emphasise how experience comes to be embodied and
articulated through different media - bodies, speech, text, and images. Moreover, we suggest that paying closer
attention to these media provides opportunities for enhancing our understanding of how people with different
chronic and/or terminal illnesses use or do not use different forms of peer support - and in particular online ones as a source of health-related experiential knowledge. Some of the implications of this are discussed in the specific
context of people diagnosed with incurable neurodegenerative conditions characterised by visible physical
deterioration and associated emotional distress.
Language : ENG
Ref ID 63
Authors : A. Minelli, C. Conte, I. Cacciatore, C. Cornacchia and F. Pinnen.
Title : Molecular mechanism underlying the cerebral effect of Gly-Pro-Glu tripeptide bound to L: -dopa in a
Parkinson's animal model
Journal : Amino Acids 2012
Abstract : Oxidative stress is a critical contributing factor to neurodegenerative disorders. Therefore, the inhibition
of ROS formation, responsible for chronic detrimental neuroinflammation, is an important strategy for preventing
the neurodegenerative disease and for neuroprotective therapy. Gly-Pro-Glu (GPE) is the N-terminal tripeptide of
insulin-like growth factor-I, which is naturally cleaved in the plasma and brain tissues. GPE has neuroprotective
effects since it crosses the blood-CSF and the functional CSF-brain barriers and binds to glial cells. It has been
shown that GPE improves motor behaviour in rats after 6-OHDA lesion, although it does not rescue dopaminergic
neurons. Thus, we hypothesized that the GPE therapeutic efficacy in a Parkinson model might be improved by
combining GPE to L: -dopa. Here, we used an animal model that represents a progressive chronic Parkinson's
disease (PD) model, characterized by high levels of oxidative stress and inflammation. We showed that the codrug, in which L: -dopa is covalently linked to the GPE tripeptide, by down-regulating the expression of
inflammatory genes, decreases the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced inflammatory
response and, by up-regulating tyrosine hydroxylase, reduces MPTP-induced neurotoxicity. Furthermore, by
determining the nuclear translocation/activation of Nrf2 and NF-kappaB, we showed that systemic administration
of the co-drug activates Nrf2-induced antioxidant response while suppressing NF-kappaB inflammatory pathway.
Data suggest that the binding of L: -dopa to GPE tripeptide might represent a promising strategy to supply L: dopa to parkinsonian patients.
Language : ENG
Ref ID 64
Authors : S. Montel, L. Albertini and E. Spitz.
Title : Coping strategies in relation to quality of life in amyotrophic lateral sclerosis
Journal : Muscle Nerve 2012 vol.45 part 1 pp 131-134
Abstract : INTRODUCTION: The aim of this study was to examine the coping strategies of 49 patients with
amyotrophic lateral sclerosis (ALS) and the relationships of these strategies to their perceived health-related
quality of life (HRQoL). METHODS: Forty-nine subjects were assessed for collection of demographic and medical
data. Each one was then asked to complete a questionnaire of coping strategies (Brief COPE) as well as a
questionnaire of health-related duality of life (36-item Short Form). RESULTS: Correlation analysis showed strong
relationships between some coping and HRQoL dimensions, including: emotional support and physical functioning
(P = 0.01) and emotional role functioning (P = 0.02); venting and mental health (P = 0.04); positive reframing
and mental health (P = 0.03); and disengagement and emotional role functioning (P = 0.03). CONCLUSIONS: The
relationships between some coping strategies and certain dimensions of HRQoL are shown. We now understand
the usefulness of focusing on coping strategies to improve HRQoL in ALS. Muscle Nerve 45: 131-134, 2012.
Language : eng
Ref ID 65
Authors : M. Moreno-Martet, L. Mestre, F. Loria, C. Guaza, J. Fernandez-Ruiz and E. de Lago.
Title : Identification of receptors and enzymes for endocannabinoids in NSC-34 cells: Relevance for in vitro studies
with cannabinoids in motor neuron diseases
Journal : Neurosci.Lett. 2011
Abstract : NSC-34 cells, a hybridoma cell line derived from the fusion of neuroblastoma cells with mice spinal cord
cells, have been widely used as an in vitro model for the study of motor neuron diseases [i.e. amyotrophic lateral
sclerosis (ALS)]. In the present study, they were used to characterize different elements of the cannabinoid
signaling system, which have been reported to serve as targets for the neuroprotective action of different natural
and synthetic cannabinoid compounds. Using RT-PCR, Western blotting and immunocytochemistry, we first
identified the presence of the cannabinoid CB(1) receptor in these cells. As expected, CB(2) receptor is not
expressed in this neuronal cell line, a result that is concordant with the idea that this receptor type is preferentially
expressed in glial elements. Diacylglycerol-lipase (DAGL) and N-arachidonoylphosphatidylethanolaminephospholipase D (NAPE-PLD), the enzymes that synthesize endocannabinoids, have also been detected in these
cells using RT-PCR, and the same happened with the endocannabinoid-degrading enzymes fatty acid amide
hydrolase (FAAH) and monoacylglycerol-lipase (MAGL). The presence of the CB(1) receptor in these cells supports
the idea that this receptor may play a role in the regulation of cellular survival face to excitotoxic injury.
Interestingly, the expression of CB(1) receptor (and also the FAAH enzyme) was strongly up-regulated after
differentiation of these cells, as previously reported with glutamate receptors. No changes were found for NAPEPLD, DAGL and MAGL. Assuming that glutamate toxicity is one of the major causes of neuronal damage in ALS and
other motor neurons diseases, the differentiated NSC-34 cells might serve as a useful model for studying
neuroprotection with cannabinoids in conditions of excitotoxic injury, mitochondrial malfunctioning and oxidative
stress.
Language : ENG
Ref ID 66
Authors : M. Moshahid Khan, S. S. Raza, H. Javed, et al.
Title : Rutin Protects Dopaminergic Neurons from Oxidative Stress in an Animal Model of Parkinson's Disease
Journal : Neurotox Res. 2011
Abstract : This study was undertaken to investigate the neuroprotective effects of rutin (vitamin P) on 6hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. Oxidative stress and inflammation is an
important event, play a crucial role in neurodegenerative diseases. Rutin has been shown to have antioxidant and
anti-inflammatory actions, and thus was tested for its beneficial effects using 6-OHDA-induced PD rat model. Male
Wistar rats were pre-treated with rutin (25 mg/kg bwt, orally) for 3 weeks and subjected to unilateral intrastriatal
injection of 6-OHDA (10 mug in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats
were tested for neurobehavioral activity, and were killed after 4 weeks of 6-OHDA infusion for the estimation of
thiobarbituric acid reactive substances, glutathione, and its dependent enzymes (glutathione peroxidase and
glutathione reductase), dopamine (DA) and its metabolite 3,4-dihydroxyphenyl acetic acid. The increase in 6OHDA-induced rotations and deficits in locomotor activity and motor coordination and decrease in antioxidant
level, DA content and its metabolite and increase in the number of dopaminergic D2 receptors in striatum were
protected significantly with lesioned group pre-treated with rutin. These findings were further supported by the
histopathological and immunohistochemical findings in the substantia nigra that showed that rutin protected
neurons from deleterious effects of 6-OHDA. These results suggest that the consumption of rutin, which is novel
vitamin, may have the possibility of protective effect against the neurological disorder such as PD.
Language : ENG
Ref ID 67
Authors : H. E. Moss, L. McCluskey, L. Elman, et al.
Title : Cross-sectional evaluation of clinical neuro-ophthalmic abnormalities in an amyotrophic lateral sclerosis
population
Journal : J.Neurol.Sci. 2011
Abstract : OBJECTIVE: Ocular motility abnormalities may be a marker of neuro-degeneration beyond motor
neurons in amyotrophic lateral sclerosis (ALS). We formally compared clinical neuro-ophthalmic abnormalities in
ALS patients and a control population. METHODS: Patients attending a multidisciplinary ALS clinic (n=63, age
60.8+/-16.4years) and their caregivers serving as controls (n=37, ages 55.0+/-12.7years) participated in this
cross-sectional study. Visual acuity was assessed. Video recordings of a standardized ocular motility exam
including gaze fixation, voluntary saccades, reflex saccades, smooth pursuit, eyelid opening and Bell's
phenomenon were rated by two senior neuro-ophthalmologists who were masked to subject group. RESULTS:
Visual acuity was lower in ALS patients versus control subjects (OR 0.81 (0.71-0.93), p=0.003, logistic
regression). Inter- and intra-rater reliability for ocular motility examination ratings were good (Cohen's
Kappa>0.6). Findings observed only in ALS subjects included gaze impersistence (14%, p=0.01), moderately or
severely restricted voluntary upgaze (13%, p=0.01), and moderate or severe eyelid opening apraxia (27%,
p=0.0002). Accounting for age, moderately or severely saccadic horizontal smooth pursuits distinguished ALS
from control subjects (OR 3.6 (1.2-10.9), p=0.02, logistic regression). CONCLUSIONS: Clinical findings of
decreased visual acuity, gaze impersistence, voluntary upgaze restriction, eyelid opening apraxia, and saccadic
horizontal smooth pursuits are more frequent in patients with ALS than in similar-aged controls. These findings are
potential clinical markers of neurodegeneration beyond upper and lower motor neuron disease in ALS. Further
study is warranted regarding their application to disease categorization and outcomes assessment.
Language : ENG
Ref ID 68
Authors : H. Mrabet, A. Borhani-Haghighi, E. Koseoglu, et al.
Title : Association of amyotrophic lateral sclerosis and Behcet's disease: is there a relationship? A multi-national
case series
Journal : Clin.Rheumatol. 2012
Abstract : Neurological involvement may be seen in 5-30% of the patients with Behcet's disease (BD).
Occasionally, parenchymal neurological involvement in BD can present as a spinal cord syndrome. However, motor
neuron disease-like presentation is extremely uncommon. Here we are reporting five patients (all male; median
age, 38) fulfilling both International Study Group criteria for BD and El Escorial criteria for amyotrophic lateral
sclerosis (ALS). These patients were identified by a questionnaire sent to the members of the Neuro-Behcet Study
Group of the International Study Group for BD. Three out of five patients had only motor presentations. In two
patients, sensory and urinary manifestations were present as well. Spinal cord MRIs were normal in all, and brain
MRIs were normal in four patients; one patient had nonspecific white matter changes. Two patients passed away
1-3 years after diagnosis of ALS, and two patients were lost to follow-up 3 and 11 years after admission; one
patient is still alive 3 years after onset. The patients that are presented here might represent a rare form of
neurological involvement in BD as well as sole coincidence. Larger prospective series are needed to further answer
this issue.
Language : ENG
Ref ID 69
Authors : R. B. Mythri and M. S. Bharath.
Title : Curcumin: A Potential Neuroprotective Agent in Parkinson's Disease
Journal : Curr.Pharm.Des. 2012
Abstract : Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a
movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in
the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the
current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these
drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term
treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most
importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies
involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for
adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary
spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer
properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in
different experimental models of PD strongly support the clinical application of curcumin in PD. The current review
explores the therapeutic potential of curcumin in PD.
Language : ENG
Ref ID 70
Authors : S. Navailles and P. De Deurwaerdere.
Title : Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation
of the Subthalamic Nucleus or Levodopa in Parkinson's Disease
Journal : Mol.Neurobiol. 2012
Abstract : Although they are effective at treating the motor impairments that are the core symptoms of
Parkinson's disease, current treatments, namely L: -3,4-dihydroxyphenylalanine (L: -DOPA), the gold standard
medication and high-frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood
alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to
abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies
in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It
has also been shown that the serotonergic system both plays a major role in the mechanism of action of the
current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release
in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in
L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to
dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by
newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and
metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system
activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies
targeting the serotonergic system are being developed and could be decisive in limiting L: -DOPA-induced
dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies.
Language : ENG
Ref ID 71
Authors : M. A. Orsini.
Title : Severity and functional ability scale for amyotrophic lateral sclerosis patients
Journal : Arq.Neuropsiquiatr. 2012 vol.70 part 1 pp 79-80 Language : eng
Ref ID 72
Authors : R. Ortner, F. Aloise, R. Pruckl, et al.
Title : Accuracy of a P300 speller for people with motor impairments: a comparison
Journal : Clin.EEG Neurosci. 2011 vol.42 part 4 pp 214-218
Abstract : A Brain-Computer Interface (BCI) provides a completely new output pathway that can provide an
additional option for a person to express himself/herself if he/she suffers a disorder like amyotrophic lateral
sclerosis (ALS), brainstem stroke, brain or spinal cord injury or other diseases which impair the function of the
common output pathways which are responsible for the control of muscles. For a P300 based BCI a matrix of
randomly flashing characters is presented to the participant. To spell a character the person has to attend to it and
to count how many times the character flashes. Although most BCIs are designed to help people with disabilities,
they are mainly tested on healthy, young subjects who may achieve better results than people with impairments.
In this study we compare measurements, performed on people suffering motor impairments, such as stroke or
ALS, to measurements performed on healthy people. The overall accuracy of the persons with motor impairments
reached 70.1% in comparison to 91% obtained for the group of healthy subjects. When looking at single subjects,
one interesting example shows that under certain circumstances, when it is difficult for a patient to concentrate on
one character for a longer period of time, the accuracy is higher when fewer flashes (i.e., stimuli) are presented.
Furthermore, the influence of several tuning parameters is discussed as it shows that for some participants
adaptations for achieving valuable spelling results are required. Finally, exclusion criteria for people who are not
able to use the device are defined.
Language : eng
Ref ID 73
Authors : M. Otto, R. Bowser, M. Turner, et al.
Title : Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS
Journal : Amyotroph Lateral Scler. 2012 vol.13 part 1 pp 1-10
Abstract : Abstract Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral
sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining
prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers
exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for
independent verification. This review considers the potential routes to the discovery of neurochemical markers in
ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter
collaboration, validation and ultimately clinical translation.
Language : ENG
Ref ID 74
Authors : N. Pavese.
Title : PET studies in Parkinson's disease motor and cognitive dysfunction
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S96-9
Abstract : Positron emission tomography (PET) has led to significant advances in the knowledge of the
neurobiology and pathophysiology of Parkinson's disease (PD) and has also greatly contributed to the
understanding of potential mechanisms involved in the development of treatmentinduced complications. Initially,
PET was mostly used to assess in vivo the severity of the nigrostriatal dopaminergic dysfunction and the resulting
motor symptomatology in PD. It has been demonstrated that PET measurements of putaminal dopaminergic
function, as measured by [(18)F]-Fluorodopa uptake, correlate well with stages of disease and symptom severity
in PD patients, particularly with bradykinesia and rigidity. Analysis of metabolic changes across the brain has
identified specific brain networks associated with the main motor features of the disease, including bradykinesia
and tremor. In more recent years, the growing availability of new imaging radiotracers for monoaminergic and
cholinergic neurons has enabled the evaluation of the non-dopaminergic brain pathways that are likely to be
involved in the pathophysiology of non motor symptoms of PD, including depression, fatigue, sleep disorders, and
cognitive impairment. Finally, beta-amyloid imaging agents have been used to assess the influence of coexistent
cortical Alzheimer pathology in PD. This review summarizes the findings from PET studies that have investigated
pathophysiology and treatment of motor dysfunction and cognitive impairment in PD.
Language : eng
Ref ID 75
Authors : S. Phani, J. D. Loike and S. Przedborski.
Title : Neurodegeneration and Inflammation in Parkinson's disease
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S207-9
Abstract : Parkinson's disease (PD) is characterized by the progressive degeneration of dopamine (DA) neurons of
the substantia nigra pars compacta (SNpc) accompanied by a buildup of proteinaceous aggregates termed Lewy
bodies (LB). In addition to protein aggregation and the loss of DA signaling, PD is also characterized by an active
immune response. T-cell infiltration accompanies activated microglial and astrocytic accumulation in and around
the SNpc. Although potentially beneficial, microglial activation is most likely responsible for furthering disease
pathology and DA neuron degeneration through the release of harmful substances such as pro-inflammatory
cytokines, reactive oxidative species and reactive nitrogen species. Activation of the NF-kappaB death pathway
has been shown to occur following microglial activation related release of Cox-2, IL-1beta, and Toll-like receptor
activation, resulting in increased degeneration of DA neurons of the SNpc. Blockade of microglial activation can
lead to DA neuron protection in animal models of PD; however, clinical application of anti-inflammatory drugs has
not yielded similar benefits. Future therapeutic designs must take into account the multifactorial nature of PD,
including the varied roles of the adaptive and innate immune responses.
Language : eng
Ref ID 76
Authors : S. Pinto, M. Swash and M. de Carvalho.
Title : Respiratory exercise in amyotrophic lateral sclerosis
Journal : Amyotroph Lateral Scler. 2012 vol.13 part 1 pp 33-43
Abstract : Abstract We have evaluated the potential role of respiratory exercise by implementing specific
inspiratory muscle training in a selected population of early-affected amyotrophic lateral sclerosis (ALS) patients.
We studied 26 patients with ALS with normal respiratory function using two groups of patients in a parallel,
control-group, randomized, delayed-start design. Patients in the first group (G1) started the active inspiratory
exercise programme at entry and were followed for eight months, while the second group (G2) of patients
followed a placebo exercise programme for the first four months and then active exercise for the second fourmonth period. The primary outcome measure was the ALSFRS. Respiratory tests, neurophysiological
measurements, fatigue and quality of life scales were secondary outcomes. Analysis of covariance was used to
compare changes between and within groups. Results showed that there was no significant difference between the
two patient groups. Within-group analysis suggested that inspiratory exercise promotes a transient improvement
in the respiratory subscore and in the maximal voluntary ventilation, peak expiratory flow, and sniff inspiratory
pressure. In conclusion, there was no clear positive or negative outcome of the respiratory exercise protocol we
have proposed, but we cannot rule out a minor positive effect. Exercise regimes merit more detailed clinical
evaluation in ALS.
Language : eng
Ref ID 77
Authors : S. M. Poulose, D. R. Fisher, J. A. Larson, et al.
Title : Anthocyanin-rich acai (Euterpe oleracea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in
mouse brain BV-2 microglial cells
Journal : J.Agric.Food Chem. 2012
Abstract : Age-related diseases of the brain compromise memory, learning and movement, and are directly linked
with increases in oxidative stress and inflammation. Previous research has shown that supplementation with
berries can modulate signaling in primary hippocampal neurons or BV-2 mouse microglial cells. Because of their
high polyphenolic content, we explored the protective effect of acai (Euterpe oleracea Mart.) fruit pulp fractions on
BV-2 mouse microglial cells. Freeze-dried acai pulp was fractionated using solvents with different polarity and
analyzed using HPLC for major anthocyanins and other phenolics. Fractions extracted using methanol (MEOH) and
ethanol (ETOH) were particularly rich in anthocyanins such as cyanidin, delphinidin, malvidin, pelargonidin and
peonidin, where as the fraction extracted using acetone (ACE) was rich in other phenolics such as catechin, ferulic
acid, quercetin, resveratrol, synergic and vanillic acids. Studies were conducted to investigate the mitigating
effects of acai pulp extracts on lipopolysaccharide (LPS, 100 ng/mL) induced oxidative stress and inflammation;
treatment of BV2 cells with acai fractions resulted in significant (p<0.05) decreases in nitrite production,
accompanied by a reduction in inducible nitrous oxide synthase (iNOS) expression. The inhibition pattern was
emulated with the ferulic acid content among the fractions. The protection of microglial cells by acai pulp extracts,
particularly that of MEOH, ETOH and ACE fractions, was also accompanied by the significant concentrationdependent reduction in cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (p38-MAPK), tumor
necrosis factor-alpha (TNFalpha) and nuclear factor kappa-b (NF-kappaB). The current study offers valuable
insights into the protective effects of acai pulp fractions on brain cells, which could have implications for improved
cognitive and motor functions.
Language : ENG
Ref ID 78
Authors : S. N. Pressey, D. A. Smith, A. M. Wong, F. M. Platt and J. D. Cooper.
Title : Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick
type C1 mice
Journal : Neurobiol.Dis. 2011
Abstract : Niemann-Pick disease type C (NPC) is an inherited lysosomal storage disease characterised by
accumulation of cholesterol and glycosphingolipids. NPC patients suffer a progressive neurodegenerative
phenotype presenting with motor dysfunction, mental retardation and cognitive decline. To examine the onset and
progression of neuropathological insults in NPC we have systematically examined the CNS of a mouse model of
NPC1 (Npc1(-/-) mice) at different stages of the disease course. This revealed a specific spatial and temporal
pattern of neuropathology in Npc1(-/-) mice, highlighting that sensory thalamic pathways are particularly
vulnerable to loss of NPC1 resulting in neurodegeneration in Npc1(-/-) mice. Examination of markers of
astrocytosis and microglial activation revealed a particularly pronounced reactive gliosis in the thalamus early in
the disease, which subsequently also occurred in interconnected cortical laminae at later ages. Our examination of
the precise staging of events demonstrate that the relationship between glia and neurons varies between brain
regions in Npc1(-/-) mice, suggesting that the cues causing glial reactivity may differ between brain regions. In
addition, aggregations of pre-synaptic markers are apparent in white matter tracts and the thalamus and are likely
to be formed within axonal spheroids. Our data provide a new perspective, revealing a number of events that
occur prior to and alongside neuron loss and highlighting that these occur in a pathway dependent manner.
Language : ENG
Ref ID 79
Authors : J. C. Ren, X. L. Fan, X. A. Song, X. H. Zhao, M. X. Chen and L. Shi.
Title : Prolonged hindlimb unloading leads to changes in electrophysiological properties of L5 dorsal root ganglion
neurons in rats after 14 days
Journal : Muscle Nerve 2012 vol.45 part 1 pp 65-69
Abstract : Introduction: The purpose of this study was to evaluate the electrophysiological changes observed in
dorsal root ganglion (DRG) neurons in a simulated weightlessness rat model and to assess the mechanisms
involved in these changes. Methods: The simulated weightlessness model was created by hindlimb unloading (HU).
Whole-cell patch-clamp recordings, conduction velocity measurement, and ultrastructural observation were
performed. Results: In the HU rats, the action potentials had a longer duration and slower falling rate, but there
was no significant effect on amplitude or rate of rise. HU also induced lowering of rheobase and of the threshold
potential, making the cells more excitable. The conduction velocities in the proximal branches of ganglion cells
were also decreased, and some degenerative changes in the myelin sheath were noted. Conclusions: This study
provides evidence of plasticity of DRG neurons induced by HU. The changes observed might contribute to impaired
motor performance in rats submitted to HU. Muscle Nerve 45: 65-69, 2012.
Language : eng
Ref ID 80
Authors : G. E. Rodriguez, D. M. Gonzalez, G. M. Monachelli, J. J. Costa, A. F. Nicola and R. E. Sica.
Title : Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral
sclerosis
Journal : Arq.Neuropsiquiatr. 2012 vol.70 part 1 pp 40-44
Abstract : OBJECTIVES: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes
and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the
status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin
abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in
keratinocytes from patients with SALS and healthy controls. METHODS: Our study was based on the analysis of
112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy.
RESULTS: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the
organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS
mitochondria presented cristolysis and breakage of the outer membrane. CONCLUSIONS: Mitochondrial
dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The
analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually,
the effectiveness of current therapies for SALS.
Language : eng
Ref ID 81
Authors : J. Sasabe, Y. Miyoshi, M. Suzuki, et al.
Title : D-Amino acid oxidase controls motoneuron degeneration through D-serine
Journal : Proc.Natl.Acad.Sci.U.S.A. 2012 vol.109 part 2 pp 627-632
Abstract : Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of
motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective
motoneuronal death in ALS. d-Serine, an endogenous coagonist of N-methyl-d-aspartate receptors, exacerbates
motoneuronal death and is increased both in patients with sporadic/familial ALS and in a G93A-SOD1 mouse
model of ALS (mSOD1 mouse). More recently, a unique mutation in the d-amino acid oxidase (DAO) gene,
encoding a d-serine degrading enzyme, was reported to be associated with classical familial ALS. However,
whether DAO affects the motoneuronal phenotype and d-serine increase in ALS remains uncertain. Here, we show
that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal
degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major
inputs to the lower motoneurons, predominantly contributes to the d-serine increase in the mSOD1 mouse. The
DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate
receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal
role in motoneuron degeneration through d-serine regulation and that inactivity of DAO is a common feature
between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of
reducing d-serine or controlling DAO activity in ALS should be tested in future studies.
Language : eng
Ref ID 82
Authors : A. Sauerbeck, R. Hunter, G. Bing and P. G. Sullivan.
Title : Traumatic brain injury and trichloroethylene exposure interact and produce functional, histological, and
mitochondrial deficits
Journal : Exp.Neurol. 2011
Abstract : Mitochondria play a pivotal role in the development of pathology associated with Parkinson's disease
(PD), traumatic brain injury (TBI), and following exposure to the environmental toxin trichloroethylene (TCE).
Evidence from humans indicates that both TBI and TCE can play a role in the development of PD and that each of
these insults result in significant mitochondrial dysfunction. In the current studies we hypothesized that exposure
to both TCE and TBI would result in increased pathology associated with PD. To test this hypothesis, 16 week old
male Fischer 344 rats were administered TCE for either one or two weeks by oral gavage. Following exposure to
TCE, rats were subjected to either a sham, mild (1.0mm), or moderate (2.0mm) controlled cortical impact TBI.
Given the strong connection between mitochondrial function and PD, TBI, and TCE, tissue from the striatum and
substantia nigra were analyzed 6h after the TBI. Neither TCE exposure, TBI, nor the combination of the two insults
resulted in mitochondrial deficits at 6h post-TBI in the substantia nigra. Unlike the substantia nigra, the striatum
exhibited significant mitochondrial dysfunction. Exposure to TCE alone for two weeks resulted in approximately a
75% reduction in mitochondrial function (p<0.05) in the striatum whereas TBI alone resulted in approximately a
30% reduction in striatal mitochondrial function. Following 1 week exposure to TCE followed by TBI, there was a
significant reduction (50%) in mitochondrial function (p<0.05) which required the presence of both insults.
Beginning 12days after the injury significant motor impairment was observed with Rotarod testing. Animals
exposed to TCE and a moderate TBI exhibited performance which was approximately 50% of controls (p<0.01).
Cylinder testing revealed that at 30days post-injury animals exposed to TCE and a moderate TBI also had about a
34% reduction in the usage of the contralateral fore paw and this impairment was significantly worse than both
control animals and animals exposed to TCE and a mild TBI (p<0.05). At 30 days post-injury there was a 13-17%
reduction in the number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (p<0.05), which was
the result of protein loss and not cell death. Loss of TH positive neurons did not result in changes in striatal TH
fiber density or levels of the dopamine transporter or type-2 dopamine receptor. Additionally, exposure to TCE
prior to the TBI did not increase the loss of cortical tissue, indicating regional specificity for TCE induced deficits.
These studies provide further evidence for the connection between TCE, TBI, and PD and lend support to the
concept that PD develops from a multifactorial injury scenario.
Language : ENG
Ref ID 83
Authors : N. Sawa, H. Kataoka, K. Sugie, et al.
Title : Clinical analysis and outcomes of amyotrophic lateral sclerosis with demyelinating polyneuropathy
Journal : Amyotroph Lateral Scler. 2012 vol.13 part 1 pp 125-131
Abstract : Abstract Abnormalities of both motor and sensory nerve action potentials, similar to those found in
demyelinating polyneuropathy, may occur in patients with amyotrophic lateral sclerosis (ALS). We analyzed the
clinical features of unusual ALS patients with demyelinating polyneuropathy (DPN) to delineate the characteristics
and outcomes of this rare condition. We reviewed three ALS patients with DPN who were confirmed to meet the
electrophysiological nerve conduction criteria for DPN among 157 patients with ALS. At the initial neurological
examination, one patient had both subjective sensory symptoms and abnormal results of sensory examinations,
and one patient had sensory symptoms. Motor weakness of the limbs was present in all patients, and fasciculation
was present in two patients. Anti-GalNAc-GD1a IgG antibodies were evident in one. Sural nerve biopsy showed a
moderate, marginal reduction in myelin thickness, and teased fiber analysis revealed segmental demyelination and
remyelination, but axonal degeneration was found in one patient. The mean interval from disease onset to
respiratory failure or death in our three patients and seven previously documented ALS patients with DPN was
43.1 +/- 18.7 months. Our findings suggest that survival in ALS with DPN is similar to that in classic ALS.
Language : eng
Ref ID 84
Authors : V. Selvaraj, P. Jiang, O. Chechneva, U. G. Lo and W. Deng.
Title : Differentiating human stem cells into neurons and glial cells for neural repair
Journal : Front.Biosci. 2012 vol.17 pp 65-89
Abstract : Research on the biology of adult stem cells, embryonic stem cells and induced pluripotent stem cells, as
well as cell-based strategies for treating nervous system disorders has begun to create the hope that these cells
may be used for therapy in humans after injury or disease. In animal models of neurological diseases,
transplantation of stem cells or their derivatives can improve function not only due to direct replacement of lost
neurons or glia, but also by providing trophic support. Despite intense research efforts to translate these studies
from the bench to bedside, critical problems remain at several steps in this process. Recent technological
advancements in both the derivation of stem cells and their directed differentiation to lineage-committed
progenitors have brought us closer to therapeutic applications. Several preclinical studies have already explored
the behavior of transplanted cells with respect to proliferation, migration, differentiation and survival, especially in
complex pathological disease environments. In this review, we examine the current status, progress, pitfalls, and
potential of these stem cell technologies, focusing on directed differentiation of human stem cells into various
neural lineages, including dopaminergic neurons, motor neurons, oligodendroglia, microglia, and astroglia, and on
advancements in cell-based regenerative strategies for neural repair and criteria for successful therapeutic
applications.
Language : eng
Ref ID 85
Authors : J. A. Solomon, A. Gianforcaro and M. J. Hamadeh.
Title : Vitamin D(3) Deficiency Differentially Affects Functional and Disease Outcomes in the G93A Mouse Model of
Amyotrophic Lateral Sclerosis
Journal : PLoS One 2011 vol.6 part 12 pp e29354
Abstract : Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death in
the central nervous system. Vitamin D supplementation increases antioxidant activity, reduces inflammation and
improves motor neuron survival. We have previously demonstrated that vitamin D(3) supplementation at 10x the
adequate intake improves functional outcomes in a mouse model of ALS. OBJECTIVE: To determine whether
vitamin D deficiency influences functional and disease outcomes in a mouse model of ALS. METHODS: At age 25 d,
102 G93A mice (56 M, 46 F) were divided into two vitamin D(3) groups: 1) adequate (AI; 1 IU D(3)/g feed) and
2) deficient (DEF; 0.025 IU D(3)/g feed). At age 113 d, tibialis anterior (TA), quadriceps (quads) and brain were
harvested from 42 mice (22 M and 20 F), whereas the remaining 60 mice (34 M and 26 F) were followed to
endpoint. RESULTS: During disease progression, DEF mice had 25% (P = 0.022) lower paw grip endurance AUC
and 19% (P = 0.017) lower motor performance AUC vs. AI mice. Prior to disease onset (CS 2), DEF mice had 36%
(P = 0.016) lower clinical score (CS) vs. AI mice. DEF mice reached CS 2 six days later vs. AI mice (P = 0.004),
confirmed by a logrank test which revealed that DEF mice reached CS 2 at a 43% slower rate vs. AI mice (HR =
0.57; 95% CI: 0.38, 1.74; P = 0.002). Body weight-adjusted TA (AI: r = 0.662, P = 0.001; DEF: r = 0.622, P =
0.006) and quads (AI: r = 0.661, P = 0.001; DEF: r = 0.768; P<0.001) weights were strongly correlated with age
at CS 2. CONCLUSION: Vitamin D(3) deficiency improves early disease severity and delays disease onset, but
reduces performance in functional outcomes following disease onset, in the high-copy G93A mouse.
Language : eng
Ref ID 86
Authors : C. Spagnoli and C. De Sousa.
Title : Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease - treatable motor neuron diseases of
childhood
Journal : Dev.Med.Child Neurol. 2011 Language : ENG
Ref ID 87
Authors : H. Stewart, N. J. Rutherford, H. Briemberg, et al.
Title : Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene
on chromosome 9p
Journal : Acta Neuropathol. 2012
Abstract : Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of
the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic
lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the
C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented
with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset,
compared to those without this mutation. Dementia was significantly more common in ALS patients and families
with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the
members of individual families with the mutation. The associated neuropathology was a combination of ALS with
TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific
feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in
a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation
as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical
and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.
Language : ENG
Ref ID 88
Authors : X. Sun, Z. Xiong, Y. Zhang, et al.
Title : Harpagoside attenuates MPTP/MPP(+) induced dopaminergic neurodegeneration and movement disorder via
elevating glial cell line-derived neurotrophic factor
Journal : J.Neurochem. 2011
Abstract : Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the loss of
dopaminergic neurons in the substantia nigra pars compacta. New therapeutic approaches aiming at delaying or
reversing the neurodegenerative process are under active investigations. In this work, we found that harpagoside,
an iridoid purified from the Chinese medicinal herb Scrophularia ningpoensis, could not only prevent but also
rescue the dopaminergic neurodegeneration in MPTP/MPP(+) intoxication with promising efficacy. Firstly, in
cultured mesencephalic neurons, harpagoside significantly attenuated the loss of TH-positive neuron numbers and
the shortening of axonal length. Secondly, in a chronic MPTP mouse model, harpagoside dose-dependently
improved the loco-motor ability (rotarod test), increased the TH-positive neuron numbers in the substantia nigra
pars compacta (unbiased stereological counting) and increased the striatal DAT density ((125) I-FP-CIT
autoradiography). Thirdly, harpagoside markedly elevated the GDNF mRNA and GDNF protein levels in
MPTP/MPP(+) lesioned models. However, the protecting effect of harpagoside on the dopaminergic degeneration
disappeared when the intrinsic GDNF action was blocked by either the RET inhibitor PP1 or the neutralizing antiGDNF antibody. Taken together, we conclude that harpagoside attenuates the dopaminergic neurodegeneration
and movement disorder mainly through elevating glial cell line-derived neurotrophic factor. (c) 2011 The Authors
Journal of Neurochemistry(c) 2011 International Society for Neurochemistry.
Language : ENG
Ref ID 89
Authors : F. Tanaka, K. Ikenaka, M. Yamamoto and G. Sobue.
Title : Neuropathology and omics in motor neuron diseases
Journal : Neuropathology 2011
Abstract : Motor neuron diseases, including amyotrophic lateral sclerosis (ALS), are devastating disorders and
effective therapies have not yet been established. One of the reasons for this lack of therapeutics, especially in
sporadic ALS (SALS), is attributed to the absence of excellent disease models reflecting its pathology. For this
purpose, identifying important key molecules for ALS pathomechanisms and developing disease models is crucial,
and omics approaches, including genomics, transcriptomics and proteomics, have been employed. In particular,
transcriptome analysis using cDNA microarray is the most popular omics approach and we have previously
identified dynactin-1 as an important molecule downregulated in the motor neurons of SALS patients from the
early stage of the disease. Dynactin-1 is also known as a causative gene in familial ALS (FALS). Dynactin-1 is a
major component of the dynein/dynactin motor protein complex functioning in retrograde axonal transport. In
motor neuron diseases as well as other neurodegenerative diseases, the role of axonal transport dysfunction in
their pathogenesis always draws attention, but its precise mechanisms remain to be fully elucidated. In this
article, we review our previous omics approach to SALS and the role of dynactin-1 in the pathogenesis of ALS.
Finally, we emphasize the need for creating novel SALS disease models based on the results of omics analysis,
especially based on the observation that dynactin-1 gene expression was downregulated in SALS motor neurons.
Language : ENG
Ref ID 90
Authors : E. Tobinick.
Title : Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer's
Disease
Journal : Curr.Alzheimer Res. 2011
Abstract : Excess tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Alzheimer's disease(AD).
Clinical improvement following perispinal administration of etanercept in patients with Alzheimer's disease and
other forms of dementia and brain dysfunction is characteristically evident within minutes. The rapidity and
constellation of the clinical effects across multiple domains (cognition, mood, memory, motor function, and
attention) suggest they are mediated by non-synaptic signaling mechanisms previously unrecognized for
etanercept. These mechanisms likely extend beyond the known roles of TNF as a gliotransmitter that modulates
synaptic strength, synaptic scaling, and AMPA receptor trafficking. Preliminary basic science and clinical
investigation suggests that perispinal administration of etanercept may lead to its rapid penetration into the
cerebrospinal fluid (CSF) within the cerebral ventricles. Diffusion of large molecules into the periventricular brain
parenchyma is known to occur, but this process may not be sufficient to explain the rapidity of the clinical effects.
There exist populations of cells, including CSF-contacting neurons and modified ependymal cells called tanycytes,
that have receptive surfaces in direct contact with the CSF. It is hypothesized that the rapid clinical effects of
perispinal etanercept involve non-synaptic signal transduction across the ependymal barrier and into neuronal
networks via these CSF-contacting cells. This hypothesis challenges the dogma that penetration of a therapeutic
into the cerebral parenchyma through the endothelium of the cerebral vasculature (the so-called blood- brain
barrier) is necessary to produce rapid clinical effects in AD. CSF-contacting cells may constitute a therapeutic
target for a diverse group of brain, psychiatric and spinal disorders.
Language : ENG
Ref ID 91
Authors : M. A. van Es, H. J. Schelhaas, P. W. van Vught, et al.
Title : Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
Journal : Ann.Neurol. 2011 vol.70 part 6 pp 964-973
Abstract : OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding
angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying
ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an
increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than
expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both
ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on
additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers
(13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from
Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the MantelHaenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258
individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared
to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in
patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study
demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between
ALS and PD. ANN NEUROL 2011;70:964-973.
Language : eng
Ref ID 92
Authors : V. Venkataramani, O. Wirths, H. Budka, W. Hartig, G. G. Kovacs and T. A. Bayer.
Title : Antibody 9D5 Recognizes Oligomeric Pyroglutamate Amyloid-beta in a Fraction of Amyloid-beta Deposits in
Alzheimer's Disease without Cross-Reactivity with other Protein Aggregates
Journal : J.Alzheimers Dis. 2012
Abstract : Recent evidence suggests that soluble oligomeric amyloid-beta (Abeta) assemblies are critically involved
in the pathogenesis of Alzheimer's disease (AD). We have generated a conformation-dependent monoclonal
antibody (9D5) that selectively recognizes low-molecular weight AbetapE3 oligomers, and demonstrated its
diagnostic and therapeutic potential. Here, we further characterize the specificity of this antibody by evaluating a
spectrum of neurodegeneration-related protein deposits for cross-reactivity, and by comparing the staining pattern
of 9D5 with a generic Abeta antibody that targets a linear epitope (mAb NT244), and with another conformationdependent Abeta antibody that selectively labels amyloid fibrils of various molecular weights (pAb OC). The 9D5
antibody does not cross-react with other aggregated protein deposits in brains of progressive supranuclear palsy,
corticobasal degeneration, argyrophilic grain disease, Pick's disease, Parkinson's disease, dementia with Lewy
bodies, multiple system atrophy, frontotemporal lobar degeneration or amyotrophic lateral sclerosis with TDP-43
inclusions, Creutzfeldt-Jakob disease, and vessel changes in Binswanger encephalopathy, demonstrating the
specificity of 9D5 for Abeta deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only
approximately 15% of the total Abeta plaque load in the entorhinal cortex, the CA1 region, and the temporal
neocortex. Our study further supports a possible therapeutic advantage of 9D5 by the highly specific recognition of
an epitope found only in oligomeric assemblies of AbetapE3 of AD patients. Moreover, selective binding to only a
pathogenetically relevant fraction of Abeta deposits serves as rationale for passive immunization with 9D5derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits.
Language : ENG
Ref ID 93
Authors : R. Wei, A. Bhattacharya, N. Chintalaramulu, et al.
Title : Protein misfolding, mitochondrial dysfunction and muscle loss are not directly dependent on soluble and
aggregation state of mSOD1 protein in skeletal muscle of ALS
Journal : Biochem.Biophys.Res.Commun. 2012
Abstract : Mutant superoxide dismutase 1 (mSOD1) is often found as aggregates at the outer-membrane of
mitochondria in motor neurons of various mouse models and familial amyotrophic lateral sclerosis (f-ALS)
patients. It has been postulated that disruption of mitochondrial function by physical association of misfolded
mSOD1 aggregates may actually be the trigger for initiation of degeneration of motor neurons in ALS. However, it
was not clear if the same mechanism is involved in muscle degeneration and mitochondrial dysfunction in skeletal
muscles of ALS. Recent study from our laboratory show that two skeletal muscle proteins, namely creatine kinase
(CK) and glyceraldehydes-3-phosphate dehydrogenase (GAPDH) undergo major conformational and functional
changes in the f-ALS mouse model of ALS (G93A). In this paper, we report two intriguing observations which are
as follows:(i) G93A protein does not form aggregates in skeletal muscle at any stages of disease process probably
due to high chymotrypsin-like activity of proteasome and thus G93A protein aggregates have no direct effects on
progressive loss of muscle mass and global changes in protein conformation in ALS, and (ii) the soluble G93A
protein does not have direct effects on mitochondrial dysfunction as determined by quantifying the release of
reactive oxygen species (ROS) in skeletal muscle mitochondria; instead, the proteins affected by G93A possibly
affect mitochondrial ROS release. These data strongly suggest for the first time that unlike in motor neurons, the
soluble and aggregation states of the G93A protein do not have direct effects on protein misfolding and
mitochondrial dysfunction in skeletal muscle during ALS.
Language : ENG
Ref ID 94
Authors : S. M. Weng, M. E. Bailey and S. R. Cobb.
Title : Rett syndrome: from bed to bench
Journal : Pediatr.Neonatol. 2011 vol.52 part 6 pp 309-316
Abstract : Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken
language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female
births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic
behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused
almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be
primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the
cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine,
serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic,
disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an
excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also
display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density
and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations
in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a
synaptopathy (disease of the synapse) and thus potentially amenable to rational therapeutic intervention.
Language : eng
Ref ID 95
Authors : S. Willenbrock, S. Knippenberg, M. Meier, et al.
Title : In Vivo MRI of Intraspinally Injected SPIO-labelled Human CD34+ Cells in a Transgenic Mouse Model of ALS
Journal : In Vivo 2012 vol.26 part 1 pp 31-38
Abstract : Background/Aim: Administration of stem cells is a promising novel approach for treatment of
neurodegenerative diseases. For in vivo monitoring of transplanted cells, non-invasive imaging modalities are
needed. In this study we determined the tracking efficiency of a superparamagnetic iron oxide (SPIO)-labelled
canine cell line (MTH53A) in vitro as well as the human CD34(+) umbilical cord blood stem cells (hUCBCs) in vitro
and in vivo efficiency by magnetic resonance imaging (MRI). MATERIALS AND METHODS: SPIO-labelled MTH53A
cells and hUCBCs were scanned in agar gel phantoms at 1.0 T or 7.0 T. For in vivo detection, 100,000 labelled
hUCBCs were injected into the spinal cord of a transgenic amyotrophic lateral sclerosis (ALS) mouse and scanned
at 7.0 T. RESULTS: In vitro, 100,000 MTH53A cells and 250,000 hUCBCs were visible at 1.0 T. Scanning with 7.0 T
revealed 25,000 detectable MTH53A cells. In vivo, 7.0 T MRI showed clear signals of 100,000 implanted cells.
CONCLUSION: MRI combined with SPIO nanoparticles provides valuable potential for non-invasive, non-toxic in
vivo tracking of cells implanted into the spinal cord.
Language : eng
Ref ID 96
Authors : K. L. Williams, J. A. Solski, G. A. Nicholson and I. P. Blair.
Title : Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis
Journal : Neurobiol.Aging 2011
Abstract : Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the
progressive loss of motor neurons in the motor cortex, brain stem and spinal cord. Mutations in the valosincontaining protein gene (VCP) were recently described in ALS families. Some of these families included diagnoses
of other clinical features including frontotemporal dementia, Paget's disease, inclusion body myopathy,
Parkinsonism and limb weakness. We sought to determine the prevalence of VCP mutations in Australian familial
(n = 131) and sporadic (n = 48) ALS cohorts diagnosed with classic ALS. No mutations were identified indicating
that VCP mutations are not a common cause of classic ALS among Australian cases with predominantly European
ancestry.
Language : ENG
Ref ID 97
Authors : R. Xia and Z. H. Mao.
Title : Progression of motor symptoms in Parkinson's disease
Journal : Neurosci.Bull. 2012 vol.28 part 1 pp 39-48
Abstract : Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested
by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons.
The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous
disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant
in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time,
and the cardinal motor symptoms have different rates of progression, with the disease usually progressing faster
in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of
dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of
dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced
involuntary body movements and motor complications can significantly contribute to overall disability. Further,
none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have
been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the
progression. In this article, the most recent clinical studies investigating disease progression and current progress
on the development of disease-modifying drug trials are reviewed.
Language : eng
Ref ID 98
Authors : Q. Xu, S. Shenoy and C. Li.
Title : Mouse models for LRRK2 Parkinson's disease
Journal : Parkinsonism Relat.Disord. 2012 vol.18 Suppl 1 pp S186-9
Abstract : Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucinerich-repeat-kinase 2 (LRRK2), the causative gene for PARK8 type PD with autosomal dominant inheritance, are the
most prevalent genetic causes of both familial and sporadic PD. Animal models are critical tools in the attempt to
understand the mechanisms of LRRK2-mediated pathogenesis. We have generated human Bacterial Artificial
Chromosome (BAC) mediated transgenic mouse models expressing mutant LRRK2 that robustly recapitulate the
behavioral, neurochemical and pathological features of PD. These mice develop an age-dependent decrease in
motor activity that is progressive and responds to treatment with levodopa. Pathologically, the most salient
phenotype is early axonopathy of nigrostriatal dopaminergic neurons, accompanied by hyperphosphorylated tau.
The mice also exhibit a consistent dopamine transmission deficit in both acute brain slices and live freely moving
animals. Here we will discuss LRRK2 mouse models from several laboratories, their commonalities and differences,
and offer scientific insights drawn from these studies.
Language : eng
Ref ID 99
Authors : I. Yabe, S. Tsuji-Akimoto, T. Shiga, et al.
Title : Writing errors in ALS related to loss of neuronal integrity in the anterior cingulate gyrus
Journal : J.Neurol.Sci. 2012
Abstract : Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor
neuron and various cognitive deficits including writing errors. (11)C-flumazenil (FMZ), the positron emission
tomography (PET) GABA(A) receptor ligand, is a marker of cortical dysfunction. The objective of this study was to
investigate the relationship between cognitive deficits and loss of neuronal integrity in ALS patients using (11)CFMZ PET. Ten patients with ALS underwent both neuropsychological tests and (11)C-FMZ-PET. The binding
potential (BP) of FMZ was calculated from (11)C-FMZ PET images. There were no significant correlations between
the BP and most test scores except for the writing error index (WEI), which was measured by the modified
Western Aphasia Battery - VB (WAB-IVB) test. The severity of writing error was associated with loss of neuronal
integrity in the bilateral anterior cingulate gyrus with mild right predominance (n=9; x=4mm, y=36mm, z=4mm,
Z=5.1). The results showed that writing errors in our patients with ALS were related to dysfunction in the anterior
cingulate gyrus.
Language : ENG
Ref ID 100
Authors : W. Yang and M. J. Strong.
Title : Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment
Journal : Amyotroph Lateral Scler. 2012
Abstract : Although the biological basis of frontotemporal syndromes associated with amyotrophic lateral sclerosis
(ALS) is considered to be altered metabolism of TDP-43, in ALS with cognitive impairment (ALSci) the metabolism
of tau protein is also altered. This includes neuronal hyperphosphorylation (pThr(175)). Using novel polyclonal
phospho-tau antibodies (pSer(208, 210), pThr(217) and pThr(175)) and antibodies directed against PHF tau
(pSer(202)), TDP-43 or ubiquitin, we characterized tau deposition in ALS and ALSci. In ALS, we observed
pThr(175) tau immunoreactive intraneuronal and neuritic aggregates throughout the amygdala and entorhinal
cortex. In ALSci, this extended to the anterior cingulate gyrus, superior frontal cortex and substantia nigra. The
pThr(217) antibody detected widespread astrocytic tau deposition, including punctuate or fibrillary aggregates, or
intensely immunoreactive tufted astrocytes in the superior frontal cortex, anterior cingulate gyrus, entorhinal
cortex, amygdala and basal ganglia of ALS. In ALSci, a similar but more widely distributed pThr(217) pathology
was observed. There was no correlation between the extent of pathological tau deposition and TDP-43 pathology,
although nuclear TDP-43 immunoreactivity was absent in neurons with tau pathology. In conclusion, ALSci is
unique in possessing both tau and TDP-43 pathology. The presence of widespread astrocytic tau pathology
suggests that ALSci may initially be characterized by astrocytic pathology.
Language : ENG
Ref ID 101
Authors : L. Yi, A. Donsante, M. L. Kennerson, J. F. Mercer, J. Y. Garbern and S. G. Kaler.
Title : Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related
distal motor neuropathy
Journal : Hum.Mol.Genet. 2011
Abstract : ATP7A is a P-type ATPase that regulates cellular copper homeostasis by activity at the trans-Golgi
network (TGN) and plasma membrane (PM), with the location normally governed by intracellular copper
concentration. Defects in ATP7A lead to Menkes disease or its milder variant, occipital horn syndrome, or to a
newly discovered condition, ATP7A-related distal motor neuropathy (DMN), for which the precise pathophysiology
has been obscure. We investigated two ATP7A motor neuropathy mutations (T994I, P1386S) previously associated
with abnormal intracellular trafficking. In the patients' fibroblasts, total internal reflection fluorescence (TIRF)
microscopy indicated a shift in steady-state equilibrium of ATP7A(T994I) and ATP7A(P1386S), with excess PM
localization. Transfection of Hek293T cells and NSC-34 motor neurons with the mutant alleles tagged with Venus
fluorescent protein also revealed excess PM localization. Endocytic retrieval of the mutant alleles from the PM to
the TGN was impaired. Immunoprecipitation assays revealed an abnormal interaction between ATP7A(T994I) and
p97/VCP, a ubiquitin-selective chaperone which is mutated in two autosomal dominant forms of motor neuron
disease: amyotrophic lateral sclerosis and inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). SiRNA knockdown of p97/VCP corrected ATP7A(T994I) mislocalization. Flow
cytometry documented that non-permeabilized ATP7A(P1386S) fibroblasts bound a carboxyl-terminal ATP7A
antibody, consistent with relocation of the ATP7A di-leucine endocytic retrieval signal to the extracellular surface
and partially destabilized insertion of the 8(th) transmembrane helix. Our findings illuminate the mechanisms
underlying ATP7A-related distal motor neuropathy and establish a link between p97/VCP and genetically distinct
forms of motor neuron degeneration.
Language : ENG
Ref ID 102
Authors : T. Zhang, H. Y. Hwang, H. Hao, C. Talbot Jr and J. Wang.
Title : Caenorhabditis elegans RNA-processing Protein TDP-1 Regulates Protein Homeostasis and Lifespan
Journal : J.Biol.Chem. 2012
Abstract : Transactive response DNA-binding protein (TARDBP/TDP-43), a heterogeneous nuclear
ribonucleoprotein (hnRNP) with diverse activities, is a common denominator in several neurodegenerative
disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Orthologs of
TDP-43 exist in animals ranging from mammals to invertebrates. Here we systematically studied mutant
Caenorhabditis elegans lacking the nematode TDP-43 ortholog, TDP-1. Heterologous expression of human TDP-43
rescued the defects in C. elegans lacking TDP-1, suggesting their functions are conserved. Although the tdp-1
mutants exhibited deficits in fertility, growth, and locomotion, loss of tdp-1 attenuated defects in several C.
elegans models of proteotoxicity. Loss of tdp-1 suppressed defects in transgenic C. elegans expressing TDP-43 or
Cu/Zn superoxide dismutase, both of which are associated with proteotoxicity in neurodegenerative diseases. Loss
of tdp-1 also reduced defects in mutant animals lacking the heat shock factor HSF-1. Transcriptional profiling
demonstrated that the loss of TDP-1 altered expression of genes functioning in RNA processing and protein
folding. Furthermore, the absence of tdp-1 extended lifespan in C. elegans. The lifespan extension required a
FOXO transcriptional factor DAF-16 but not HSF-1. These results suggest that the C. elegans TDP-1 has a role in
the regulation of protein homeostasis and aging.
Language : ENG
Ref ID 103
Authors : W. Zhang, R. Benmohamed, A. C. Arvanites, et al.
Title : Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in
PC12 cells
Journal : Bioorg.Med.Chem. 2011
Abstract : Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the
progressive loss of motor neurons. Currently, there is only one FDA-approved treatment for ALS (riluzole), and
that drug only extends life, on average, by 2-3months. Mutations in Cu/Zn superoxide dismutase (SOD1) are
found in familial forms of the disease and have played an important role in the study of ALS pathophysiology. On
the basis of their activity in a PC12-G93A-YFP high-throughput screening assay, several bioactive compounds have
been identified and classified as cyclohexane-1,3-dione (CHD) derivatives. A concise and efficient synthetic route
has been developed to provide diverse CHD analogs. The structural modification of the CHD scaffold led to the
discovery of a more potent analog (26) with an EC(50) of 700nM having good pharmacokinetic properties, such as
high solubility, low human and mouse metabolic potential, and relatively good plasma stability. It was also found
to efficiently penetrate the blood-brain barrier. However, compound 26 did not exhibit any significant life span
extension in the ALS mouse model. It was found that, although 26 was active in PC12 cells, it had poor activity in
other cell types, including primary cortical neurons, indicating that it can penetrate into the brain, but is not active
in neuronal cells, potentially due to poor selective cell penetration. Further structural modification of the CHD
scaffold was aimed at improving global cell activity as well as maintaining potency. Two new analogs (71 and 73)
were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency
to that of 26 in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic
candidates for ALS.
Language : ENG