Molecular Biomarkers for Amyotrophic Lateral Sclerosis
Chi-Shin Hwang1, Chia-Hung Hsieh2, Guan-Ting Liu2,3, Si-Yi Chen3,4, Johnannes SchengMing Tschen4,5, Hao-Teng Chang2,3,6*
1
Department of Neurology, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan,
Republic of China; 2Graduate Institute of Basic Medical Science and Ph.D. Program for
Aging, and 3Graduate Institute of Molecular Systems Biomedicine, Taichung, Taiwan,
Republic of China; 6China Medical University Hospital, Taichung, Taiwan, Republic of
China; 4Master Programs of Life Science, College of Life Sciences, National Chung Hsin
University, Taichung, Taiwan, Republic of China; 5Biotechnology Department, Ming Dao
University, Taichung, Taiwan, Republic of China.
*Corresponding author:
Dr Hao-Teng Chang, Graduate Institute of Molecular Systems Biomedicine, College of
Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan,
Republic of China. Tel: +886-4-22052121 ext. 7721; Fax: +886-4-22333641; E-mail:
htchang@mail.cmu.edu.tw
1
Abstract
Amyotrophic lateral sclerosis (ALS) is a complicated and devastating neurodegenerative
disease. To date, its diagnosis is still mainly based on clinical symptoms and
electromyographic findings. High rates of misdiagnosis and delayed diagnosis are the major
hurdles in ALS treatment. Thus, searching for biomarkers to improve clinical diagnosis of
ALS is a highly desirable goal. Here we review current potential biomarkers derived from the
various pathogenic mechanisms of ALS, including those involved in oxidative stress,
synaptic excitotoxicity, neuroinflammation and the autoimmune response. Oxidative stress
results from genetic mutation or an increase in protein aggregation, synaptic excitotoxicity
arising from elevated levels of glutamate and D-serine, and the neuroinflammation occurring
from elevated levels of inflammatory molecules and cytokine receptors. Some of these
biomarkers could be used for monitoring the disease progression and to assess effectiveness
of treatment for ALS. We conclude that neuroinflammation plays a crucial role in ALS,
which may lead to a better understanding of this devastating disease and ultimately to a cure.
In addition, the identification of new biomarkers would undoubtedly provide critical insights
into the pathogenesis of ALS.
Keywords: amyotrophic lateral sclerosis , biomarker , pathogenesis and autoantibody .
2
1. INTRODUCTION
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or motor neuron
disease, is the most common adult-onset neuromuscular degenerative disease in humans. Its
underlying pathology is characterized by selective loss of motor neurons in the spinal cord,
brainstem, and cerebral cortex (1). ALS usually progresses rapidly and leads to total paralysis
concomitant with respiratory failure within 2 to 5 years from diagnosis. Although ALS was
previously considered to be solely a central nervous system motor disease, it is now
recognized as a multi-system neurodegenerative disease with various extra-motor
involvements (2-4). The worldwide annual incidence of ALS is 1 to 2 per 100,000 people (5).
Approximately 10% of ALS cases are familial ALS (FALS), resulting from genetic
inheritance (6); the remaining cases are attributed to sporadic ALS (SALS), where the
cause(s) is less understood.
Although a cure for ALS does not exist, disease progression can be ameliorated.
Survival rates can be improved by early diagnosis followed by early intervention, including
medications such as Riluzole (7), multi-disciplinary care (8), the use of noninvasive positivepressure ventilation and percutaneous endoscopic gastrostomy tube feeding (9-11).
Traditionally, diagnosis of ALS is made according to neurologist’s comment primarily based
on clinical symptoms and electrophysiological findings using techniques that have been
available since the turn of the nineteenth century (12, 13). An average misdiagnosis rate of
10% has been reported (14, 15). In addition, the average delay between onset of symptoms
and confirmation of diagnosis can be as long as 13 to 18 months (16). Searching for novel
biomarkers to improve the timeliness and accuracy of the clinical diagnosis of ALS is
therefore a high priority.
For discovery of biomarkers in diagnosis or the treatment, omics approaches have been
established well, such as genomics, transcriptomics, proteomics, metabolomics and even
gene-gene and/or protein-protein interaction. A systems biology approach for identifying the
3
metabolite biomarkers was established by Wang (17). This system was developed for
comparing the different levels of serum metabolites after the acupuncture treatments using
linear programming based feature selection method. Authors specifically analyzed the high
throughput metabolome derived from the sera of subjects with acupuncture in different
acupoints. A small set of metabolites can be predicted and selected as acupuncture
biomarkers. In addition, the information of transcriptome and protein-protein interaction
could be combined for identifying the disease candidate genes (18). The gene expression
profiles could show the gene transcriptional levels and the protein-protein interaction
information could further explain the real cellular biological behaviors. Through the
combination of these two datasets, Liu and colleagues identified 34 early phase candidates
for gastric cancer. Since biomarker discovery is much important for diagnosis and disease
treatment, here we provide an overview of current researches regarding the biomarkers of
ALS.
2. REVIEW OF ALS BIOMARKERS
As shown in Table 1, many types of molecules, including amino acids, organic
chemicals, genes and proteins, would be discovered as biomarkers for ALS. Some
biomarkers have also been correlated with the disease mechanisms, such as glutamate and Dserine inducing the excitotoxicity of post synapsis, the mutants of Cu/Zn superoxide
dismutase (SOD1) inducing the neuronal death due to protein aggregation and reactive
oxygen species (ROS), transforming growth factorwe generated a subcellular localization of these biomarkers and saw that the cellular
biomarkers were distributed in nucleus, cytosol, mitochondria, membrane and extracellular
area (Figure 1). Generally, a disease would occur if a protein is located at the wrong site with
the wrong amount and/or at the wrong time. Two of the inflammatory related molecules, heat
shock proteins (HSPs) and high-mortality group box 1 (HMGB1), would be released into
4
plasma and discovered as ALS biomarkers. These protein biomarkers will be introduced in
the following sections.
Table 1. Selected studies of potential blood biomarkers for ALS
Biomarkers
Amino acids
Cu/Zn superoxide dismutase (SOD1)
Fibronectin
Hyaluronic acid
Interleukin 6
Plasma transforming growth factor-beta 1
4-Hydroxy-2,3-nonenal
Monocyte chemoattractant protein-1α
Angiogenin
Interleukin 13-positive T cells
Insulin-like growth factor (IGF) and insulinlike growth factor-binding protein (IGFBP)
Low- to high-density lipoprotein ratio
Phosphorylated axonal neurofilament H
subunit
Heat shock proteins
High-mortality group box 1
TAR DNA-binding protein 43 (TDP-43)
(RNA-binding protein FUS) FUS
Description
Increased levels of tyrosine
Decreased levels of large neutral amino
acids; no change in glutamate
Increased levels of glutamate and serine;
decreased levels of other amino acids
21q22.1 missense mutations
Decreased levels
Increased levels
Increased levels: 73% sensitive, 91%
specific
Increased levels
Increased levels
Increased levels (not vs ND)
Increased levels
Increased levels (CD4-positive and CD8positive vs HC)
Increased levels of total IGF and
decreased levels of IGFBP (not vs ND)
Increased levels
Increased levels
References
(19)
(20)
Increased levels
Increased inflammatory and
neurodegenerative processes
(33)
Genetic mutations
Genetic mutations
(35)
(35)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(27)
(28)
(29)
(30)
(31)
(32)
(34)
5
Figure 1. The subcellular distribution of the ALS biomarkers. The ROS will induce the
activation of NF-B and regulate the gene expression. The danger signals, HSPs and
HMGB1 can be released into sera of patients of ALS and may induce the neuroinflammation.
The SOD1 is a mitochondrial protein whose SOD1-G93A mutant has been developed as an
ALS mouse model. The TDP-43 and FUS are nuclear proteins for regulating the gene
expression. The membrane RAGE is a receptor for danger signals and the soluble RAGE
lower levels of RAGE observed in ALS patients.
2.1. Oxidative Stress and Copper/Zinc-Dependent Superoxide Dismutase 1 (SOD1)
Mutations in ALS
Mutations in the gene encoding copper/zinc-dependent superoxide dismutase 1
(SOD1) contribute to the disease process in FALS, and this accounts for about 20% of FALS
cases (22). These mutations lead to an increase in oxidative stress owing to SOD1
dysfunction. SOD1 is a constitutively expressed homodimer that converts superoxide to
hydrogen peroxide and water. More than 100 mutations in human SOD1 have been
6
discovered (36, 37). Most of these mutations do not affect SOD1 activity (38). However three
mutants, SOD1-G93A, SOD1-G85R and SOD1-G37R, that have been transduced into mice
induce symptoms of motor neurodegeneration (39-41), although the mechanism by which
this occurs remains unclear. The common features of the toxic SOD1-G93A and SOD1G37R mutants are protein aggregation and high levels of reactive oxygen species in
mitochondria of motor neurons (42). Despite this, there are several reasons why the loss of
SOD1 activity may not be relevant to ALS: (a) SOD1 knockout mice do not present
symptoms of motor neuron dysfunction (43); (b) levels of SOD1 activity do not correlate
with the disease in mice or humans (44); and (c) an increase in SOD1 activity in the ALS
mouse model does not accelerate or slow disease onset (45). Therefore, although SOD1
mutations may contribute to ALS, they probably are not the only cause.
2.2. Excitotoxicity from Increased Levels of Synaptic Neurotransmitters
It has been known for some time that synapses contain high levels of the
neurotransmitter glutamate, which excites N-methyl-D-aspartic acid (NMDA) signaling via
post-synaptic NMDA receptors (46). In the ALS mouse model and in humans with ALS, the
glutamate level in the brain is higher than normal (47). Riluzole is the only drug approved by
the U.S. Food and Drug Administration for slowing ALS disease progression (48, 49), and it
is thought to act by preventing stimulation of glutamine receptors, thereby reducing the effect
of excess glutamine. Another important molecule that is involved in FALS pathogenesis is
the enzyme D-amino acid oxidase (DAO), which regulates the levels of D-serine — a
neurotransmitter involved in activating NMDA receptors (50). In 2010, Belleroche et al.
discovered a unique missense mutation in the DAO gene that encoded DAOR199W in a family
with a strong inheritance of ALS. The same group also demonstrated ubiquitin aggregation
and cytotoxicity in a DAOR199W-transfected motor neuron cell line (51). This discovery
provided crucial evidence that dysfunction of DAO may result in increased D-serine levels
7
and lead to over-excitation, and ultimately increased excitotoxicity, at the postsynaptic site
(52).
2.3. Neuroinflammation
Mitchell et al. recently reported an ALS biomarker panel from the cerebrospinal fluid
(CSF) of patients with ALS that included molecules that promote inflammation and blood
vessel formation (53). They suggested that a number of inflammatory responses occur in the
central nervous system of ALS patients, and these biomarkers may reflect the levels of
neuroinflammation (53). Oxidative stress (54) and heat shock proteins (33) (HSPs) are also
thought to play an important role in the development of ALS. The HSPs belong to a family of
stress proteins associated with the general cellular stress response, and they are part of the
larger group of damage-associated molecular pattern (DAMP) molecules (55). Levels of
cytoprotective HSPs usually increase when motor neurons encounter oxidative stress (56,
57). It was found that chaperoning activity of HSPs decreases in the lumbar spinal cord but
increases or remains unchanged in clinically unaffected tissues of SOD1-G93A transgenic
mice (58).
The high mobility group box 1 (HMGB1) protein, a DAMP molecule, is a non-histone
chromosomal protein. HMGB1 is involved in maintaining nucleosome structure, and it
regulates transcription through the activation of DNA recombination and repair. It has also
been found to be a late mediator of endotoxemia and sepsis (59-61). When inflammation is
induced, HMGB1 is released from the activated macrophages and triggers the release of
proinflammatory mediators that cause cell death. HMGB1 is overexpressed in the spinal cord
of SOD1-G93A transgenic mice (34). In addition, other HMGB1-related molecules, such as
Toll-like receptor 2 (TLR-2), TLR-4, and receptor for advanced glycation end product
(RAGE), were also found at elevated levels by the studies using immunohistochemical
staining (34, 62). Both HSPs and HMGB1 belong to the class of DAMPs released by
damaged cells, and they may bind TLRs, thereby activating the inflammatory responses.
8
In addition, unpublished data from our laboratory has revealed that the serum levels of
autoantibodies against HSP60, HSP70, and HMGB1 in ALS patients were 1.64-, 1.37-, and
3.00-fold higher, respectively, than those in age-matched control subjects. This discovery
suggests that serum autoantibodies against HSP60, HSP70, and HMGB1 may serve as
biomarkers for ALS diagnosis. Furthermore, we found that the serum levels of autoantibody
against HMGB1 correlated well with the severity of ALS. This means that the serum levels
of HMGB1 may be a promising biomarker for monitoring ALS disease progression. In 2003,
Ilzecka and Stelmasiak reported that annexin-V autoantibodies could be detected in the CSF
and sera of ALS patients but not in that of controls (63). They also found that annexin-V
autoantibodies were detected only in ALS patients with bulbar onset and short disease
duration. Thus, autoantibodies may be involved in the pathogenesis of ALS and may be
related to its progression.
Levels of HSPs decrease prior to, and increase after, symptom onset in motor neurons of
SOD1-G93A transgenic mice (64). This discovery suggests that disease occurrence may
correlate with overexpression of HSPs. ALS is a progressive disease, however, motor
neurons are damaged at very early stages of disease (65), HSPs are continuously released into
the extracellular space and subsequently enter the bloodstream (66). This may lead to
induction, amplification, and release of specific autoantibodies against the HSPs by activated
B cells.
RAGE, a membrane-bound receptor, belongs to the immunoglobulin-like
superfamily, and it binds to ligands such as HMGB1, AGE, amyloid fibrils, and S100 (67). In
Alzheimer’s disease, increased levels of membrane-bound RAGE correlate well with disease
severity (68, 69). Soluble RAGE (sRAGE) is the serum polypeptide released by cleavage of
membrane-bound RAGE, and it neutralizes inflammatory factors such as HMGB1 and AGE
to reduce inflammatory symptoms (70). A recent report found that blood levels of sRAGE are
lower in ALS patients (71). The decrease of sRAGE in ALS may explain neuronal death
9
caused by DAMP molecules (72, 73). DAMP molecules and their receptors may therefore
play an important role in the pathogenic mechanisms of ALS, and neuroinflammation may
likewise play an important role in ALS onset or progression.
2.4. Other Candidate Biomarkers for ALS
The TAR DNA-binding protein 43 (TDP-43) was found in the neuron inclusion
bodies in FALS patients. In 2008, Screedharan et al. reported that a single nucleotide
polymorphism in TDP-43, encoding TDP-43M337V, induces aggregation of poly-ubiquitins
and causes neuronal damage (74). It has also been reported that the amount of TDP-43 is
elevated in the CSF of ALS patients (75). In addition, Miana-Mena et al. reported that
transthyretin levels are lower in ALS patients, particularly those with SALS (76). The extent
of post-translational modification of transthyretin, however, was higher in patients with ALS
compared to that of healthy controls (77). This result indicates that non-genetic factors may
also be involved in ALS pathogenesis.
2.5. Bioinformatics Databases for ALS Biomarkers
As mentioned in section 2.1 and 2.4, SOD1 and TDP-43 have been discovered as
important ALS biomarkers. Till now, more than 100 mutations on SOD1 are identified and
most of the TDP-43 mutations are located at the C-terminus except Ala90Val and Asp169Gly
mutations. In this section, we will introduce two ALS databases which collect all SNP
mutants of these two ALS biomarkers. ALSOD, Amyotrophic Lateral Sclerosis Online
Database, is a database collecting all SNPs of ALS biomarkers, including SOD1, ALS2,
ALS3, TDP-43 and the other 17 ALS related genes. It also includes patient information
aiming for correlating the genotype of biomarkers and the phenotype of patients with ALS
(78). Originally, ALSOD collected 97 individual ALS cases and now the database has
collected 609 cases. This database is comprehensive for ALS biomarker studies. The other
database, PRO-MINE, is an analytic tool for TDP-43 mutations (79). This database collected
all SNPs of TDP-43 gene. Since TDP-43 is not only for ALS, but also occurs in Front
10
Temporal Lobar Degeneration and Alzheimer Disease, this database was generated for
studying the neurodegenerative diseases. Besides the collection of TDP-43 SNPs, the analytic
tool can also predict the biological function of mutant TDP-43. This prediction tool makes
biologists to design the wet lab experiments for studying the relationship between mutant
TDP-43 and the neurodegenerative diseases.
CONCLUSIONS
ALS is a complex disease of the central nervous system, and identifying even a single
biomarker for the diagnosis or the monitoring of disease progression has proved elusive.
Researchers have been vigorously searching for serum biomarkers of ALS for many years,
yet no biomarker has been proved to be effective and convenient for clinical use. With the
recent progress of biomedical techniques, researchers are vigorously developing new
potential biomarkers according to the various pathogenic mechanisms of ALS. With the
identification of new biomarkers, the pathogenesis of ALS will be understood more clearly in
the near future.
Acknowledgments
This work was supported by an award from the National Science Council of Taiwan
(NSC100-2627-B-039-002 to H.-T. Chang) and an award from the Taiwan Department of
Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004).
Conflict of interest: The authors declare that they have no conflict of interest.
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