Neurodegenerative
diseases initiative
www.wellcome.ac.uk/neurodegen
The Wellcome Trust is a charity whose mission is to foster and promote research with the aim of
improving human and animal health (a charity registered in England, no. 210183). Its sole trustee
is The Wellcome Trust Limited, a company registered in England, no. 2711000, whose registered
office is at 215 Euston Road, London NW1 2BE, UK.
The Medical Research Council supports the best scientific research to improve human health.
Its work ranges from molecular level science to public health medicine and has led to pioneering
discoveries in our understanding of the human body and the diseases which affect us all.
Foreword
Lord Sutherland of Houndwood
Chair of the Neurodegenerative Diseases Initiative
Funding Committee
In a society with an increasing proportion of older people, we are presented
with new opportunities and new challenges. An opportunity to respect
and harness the contributions that older people make to society in terms
of experience, skills and wisdom; and the challenge of tackling the health
problems that they face. Among these are age-associated neurodegenerative
diseases that insidiously affect the body and brain, and which can so radically
affect the quality of their lives.
It is fitting that we should devote a significant effort in UK science to securing
a better understanding of these disorders. It has been my privilege to chair the
joint Wellcome Trust–Medical Research Council Neurodegenerative Diseases
Initiative Funding Committee, which selected the three excellent awards
highlighted here, in the face of tough competition. We were presented with
a range of exciting research proposals that sought to tackle the causes and
neurobiology of a number of neurodegenerative diseases.
Our aim was to choose teams of researchers with a clear vision on how to
tackle these neurodegenerative conditions; who would utilise their technical
skills creatively to make real progress in understanding the causes and
pathway to disease; moreover, whose work would lead to the eventual
development of novel diagnostic tools and therapeutics. These benefits will
not materialise overnight – for the scientific challenges are considerable –
but these major awards will change the research landscape in which these
disorders are being addressed.
Wellcome Trust
Neurodegenerative diseases, such
as Alzheimer’s, Parkinson’s and
motor neurone diseases, cause a
great deal of human suffering and
place considerable burden on our
health services. Better understanding
of what causes these conditions
and ever earlier identification of
their incipient onset would be
immensely beneficial. New advances
in biomedical science, ranging from
epidemiological through to molecular
and genetic studies – make this an
exceptionally timely moment to have
a focused initiative. The Wellcome
Trust is delighted to be collaborating
with the Medical Research Council
in providing major funding for this
important area of research.
Sir Mark Walport
Director, Wellcome Trust
Medical Research Council
To solve the complex puzzles posed
by neurodegenerative diseases,
investment in innovative research
is a crucial priority for the Medical
Research Council (MRC). This
initiative will help to deliver the tools
to achieve earlier diagnosis and
better treatment and prevention
strategies required to improve the
lives of the many people affected by
neurodegenerative conditions.
The awards funded under this joint
initiative will add further momentum
to the MRC’s existing investments
in neurodegeneration research.
Furthermore, these investments
will provide opportunities for further
collaboration across Europe, where
the MRC has had a leading role in
developing the new European Union
initiative in neurodegeneration and
dementia. The MRC is proud to
partner the Wellcome Trust in this
research initiative and of its success in
creating new collaborations between
the best researchers in the field.
Sir Leszek Borysiewicz
Chief Executive, MRC
Cover: Brain with Alzheimer’s disease, CT scan.
Zephyr/Science Photo Library
The NMR structure of the Abeta (amyloid beta)
peptide (red) in complex with the dimeric form
of the Abeta binding and anti-Abeta affibody.
Confocal fluorescence image of amyloid proteins in neuronal cells.
GS Kaminski Schierle, A Elder and CF Kaminski
Confocal image of an Alzheimer’s-affected brain showing a region of amyloid plaque. Medical Microscopy Sciences, Cardiff University
Alzheimer’s disease and related
neurodegenerative disorders
Mechanisms of neurotoxicity of amyloid aggregates
Summary
We will use novel methods from
physics, chemistry and biology to
discover the molecular mechanisms
that result in the death of brain cells
in Alzheimer’s disease and related
neurodegenerative disorders with
accumulation of amyloid beta and/
or tau. This information will allow the
creation of accurate and sensitive
diagnostic tests and new ways to
treat these diseases.
The problem
Alzheimer’s disease and related
disorders are increasingly common
degenerative disorders of the brain
that occur in mid-to-late adult life.
They cause impairments in memory
and intellectual function, and lead to
death within 10–15 years of diagnosis.
In the UK, 700 000 people
suffer from dementia (in around
450 000 of cases this is caused
by Alzheimer’s disease) and this
number will double to 1.4 million by
2037. These diseases cost the UK
economy about £17 billion, which
will rise to at least £50bn by 2037.
Worldwide, 37m people are affected
by these diseases – they are the
fourth leading cause of death among
adults in industrialised societies,
and are becoming an increasingly
significant healthcare problem in
developing countries.
Although we know that several
genes and environmental effects can
cause Alzheimer’s disease, we do
not know why or how they lead to
the death of nerve cells in the brain.
The paucity of knowledge about the
molecular mechanics of these diseases
has hampered the development of
sensitive and accurate tests and
effective treatments.
Peter St George-Hyslop, Principal Investigator.
The questions
The accumulation and aggregation
of two proteins in the brain – amyloid
beta and tau – is a characteristic
feature of Alzheimer’s disease,
while the accumulation of tau
alone is characteristic of a related
disorder called frontotemporal lobar
degeneration-tau type. Mutations
or variants in the amyloid precursor
protein (APP), presenilin 1 (the enzyme
that cuts APP and creates amyloid
beta) or tau genes appear to play a
crucial role in this process in some
cases. This observation has led to the
conclusion that events that cause the
accumulation of amyloid beta and tau
activate a set of downstream cellular
signalling and metabolic events that
ultimately kill nerve cells.
However, attempts using
conventional tools to understand
why brain cells are killed by the
accumulation of these proteins have
yielded confusing and conflicting
results. We still do not know what
types of aggregates formed by these
proteins are toxic to brain cells, nor
do we know how they disturb the
metabolic and signalling machinery
inside nerve cells.
Recently, we have developed
powerful biophysical and chemical
approaches that will allow us to
visualise individual aggregate
species, to watch which types of
aggregates bind to cells, and to
identify the downstream pathways
that they activate. Similarly, we have
developed a variety of cellular and
whole-organism models of these
diseases as well as computational
and systems biology tools that will
allow us to understand how these
toxic proteins affect the interlinked
network of metabolic and signalling
machinery inside nerve cells.
The project
We will apply novel tools from
physics, chemistry, computer
science, genomics, biology and
model organisms to generate
a detailed understanding of the
molecular mechanics that are
activated by the accumulation of
amyloid beta and tau, and that
ultimately lead to the death of
brain cells.
We aim to determine why and
how both amyloid beta and tau
accumulate in the brains of people
with Alzheimer’s disease, and why
the normal mechanisms for removing
aggregated proteins from brain cells
become overwhelmed. We will also
search for drug-like molecules that
stabilise aggregation-prone proteins
such as tau as potential therapies for
these diseases.
The knowledge and tools we
generate will provide a rational
basis for the future development of
diagnostic profiles that could enable
doctors to detect the disease in its
earliest stages, before irreversible
damage is done to the brain, and to
personalise and monitor treatment
programmes for individual patients,
based on the cellular networks that
have been disrupted.
Knowledge of these pathways will
also provide potential targets for the
development of new therapies to repair
these pathways, thereby preventing or
even reversing the disease.
Single-molecule imaging setup and operator.
The team
Principal investigator
Cambridge Institute for Medical
Research (CIMR), University of
Cambridge
Peter St George-Hyslop
Co-investigators
University of Cambridge
Timothy Bussey (Dept of Experimental
Psychology)
Damian Crowther (Dept of Genetics)
Christopher Dobson (Dept of
Chemistry)
Giorgio Favrin (Dept of Chemistry)
Clemens Kaminski (Dept of Chemical
Engineering & Biotechnology)
David Klenerman (Dept of Chemistry)
David Lomas (CIMR)
Cahir O’Kane (Dept of Genetics)
Stephen Oliver (Dept of Biochemistry)
David Rubinsztein (CIMR)
Lisa Saskida (Dept of Experimental
Psychology)
Gergely Toth (Dept of Chemistry)
Michele Vendruscolo (Dept of
Chemistry)
University of Bristol
Kei Cho
Graham Collingridge
Max-Planck-Unit for Structural
Molecular Biology, Germany
Eckhard Mandelkow Eva-Maria Mandelkow
University of Toronto, Canada
Paul Fraser Ekaterina Rogaeva
Gerold Schmitt-Ulms
Funding from the Wellcome Trust–MRC initiative
will allow us to turn ideas into experiments.
Christopher Shaw, Principal Investigator.
emotional support of the patient
and their family. Both disorders are
relentlessly progressive and are fatal
within three to five years on average.
Motor neurones synapsing with muscles in Drosophila development. Dr Andrea H Brand
Motor neuronE disease and
frontotemporal dementia
The role of RNA-processing proteins in neurodegeneration
Summary
Recent research on motor neurone
disease (MND) and frontotemporal
dementia (FTD) has shown that
RNA-processing proteins called
TDP-43 and FUS are deposited
in degenerating nerve cells. Rare
mutations in three genes – PGRN,
TARDBP and FUS – cause a form of
these diseases. These discoveries
allow us to make cellular and animal
models that reproduce key aspects
of the human disorders, allowing
us to explore fundamental disease
mechanisms and identify new
therapeutic targets.
The problem
FTD is the second most common
cause of dementia in the under65s, and accounts for 10 per cent
of all cases of dementia. It causes
progressive problems with personality,
behaviour and language, and
therefore differs from Alzheimer’s
disease, in which memory problems
predominate. The change in behaviour
and personality is particularly hard on
families. In 40 per cent of cases, other
family members are affected and there
is a strong genetic basis.
MND kills 1200 people in the
UK every year. It causes muscular
weakness that begins in one hand
or foot but rapidly spreads to other
parts of the body, leaving people
paralysed, unable to walk, talk and
eat. Patients feel hopeless and
helpless. MND is the single most
common reason that people seek
euthanasia. There are clear genetic
links in 10 per cent of cases, but the
genes linked to MND account for
only 5 per cent of all cases.
There is no treatment for either
FTD or MND that can significantly
improve survival. All treatment
is directed towards controlling
symptoms, and to practical and
The questions
For the past 15 years, we have
known that mutations in the MAPT
gene cause FTD with features of
Parkinsonism, and that mutations
in the SOD1 gene cause MND.
These account for only a minority
of cases, however. More recently, it
has been discovered that the RNAprocessing proteins TDP-43 and
FUS are deposited in nerve cells in
the majority of MND and FTD cases,
proving that these two diseases are
linked through their pathology.
Members of our consortium have
recently discovered mutations in the
genes PGRN, TARDBP and FUS in
families with strongly inherited forms
of FTD and MND. The challenge
now is to understand how these
mutations cause disease. We do not
know whether they cause disease
due to a loss of the protein function
or due to a new toxic property
acquired by the mutant protein.
The project
We plan to develop cellular and
animal models that will allow us to
understand what makes nerve cells
degenerate and to explore how we
might reverse this process.
Induced pluripotent stem cells in a patient with the M337V mutation in the TARDBP gene. Agnes Nishimura
To investigate the roles of
PGRN, TARDBP and FUS, we will
make cellular models that have
reduced expression of these genes
(to test a loss of function) or have
mutated genes (to test a toxic gain
of function). We will conduct similar
experiments in the fruit fly (which
will allow us to map out interacting
pathways), zebrafish (which will
allow us to rapidly screen drugs) and
mouse (which, having a mammalian
nervous system similar to humans,
should give us the closest disease
model). These models can also
be used to discover drugs that
may slow down or even arrest the
disease process in humans.
We also aim to look at the
normal function of the proteins
produced by these genes and
characterise their DNA- and
RNA-binding properties, and
the functional effects of protein
phosphorylation. Lastly we will
attempt to repair the defective
genes using gene therapy in the
cellular and animal models.
The team
Principal investigator
King’s College London (MRC
Centre for Neurodegeneration
Research)
Christopher Shaw
Co-investigators
University of California,
San Diego
Don Cleveland (Ludwig Institute
for Cancer Research)
University of Cambridge
Jernej Ule (MRC Laboratory
for Molecular Biology)
University of Dundee
John Rouse (MRC Protein
Phosphorylation Unit)
King’s College London
Jean-Marc Gallo (MRC Centre for
Neurodegeneration Research)
Noel Buckley (Centre for the Cellular
Basis of Behaviour)
Corrine Houart (MRC Centre for
Developmental Neurobiology)
University of Manchester
Stuart Pickering-Brown (Clinical
Neurosciences)
David Mann (Neuroscience Centre)
Rows of different individuals’ DNA sequences aligned at the same position
in the genome, showing single nucleotide polymorphisms (SNPs).
The consortium hopes to get a fuller understanding of
the major genetic factors underlying Parkinson’s disease.
Fluorescence deconvolution micrograph showing tau protein (red and pink), thought to play a role in Parkinson’s disease. R Bick, B Poindexter, UT Medical School/SPL
The team
Parkinson’s disease
Understanding Parkinson’s disease – lessons from biology
Principal Investigators (L–R) Nicholas Wood, Anthony Schapira and John Hardy
Summary
The cause of Parkinson’s disease
is unknown, although it is clear that
it is a disease of ageing and there
are now some established genetic
risk factors. To understand how
these factors combine, we aim to
dissect and understand the genetic
architecture of Parkinson’s disease,
to identify and characterise the
biochemical pathways involved, and
to take lessons from the biology
of people at risk of the disease to
understand its very earliest stages.
The problem
Parkinson’s disease is a common
neurodegenerative disease that
afflicts more than 2 per cent of
people aged over 75 years. In the
UK, this means there are over 100 000
people with the disease: with the
ageing population this number will
increase. The annual cost in nursinghome care for Parkinson’s disease
alone in the UK is estimated to be
about £600–800 million.
Despite tremendous progress in
the identification of genes associated
with Parkinson’s and related
disorders over the last decade, we
still have only outline and sketchy
information about the molecular
pathways involved, and their
constituents and their interactions.
Finally, if we are really to
understand the pathway to human
disease, and if we are to influence
its progression, we need to examine
the earliest phase. Thus we will
also focus on developing our
understanding of the very early
symptoms or warnings of the illness.
The questions
We hypothesise that there are
multiple causes of Parkinson’s, which
result in a very small number of
separate but converging biochemical
pathways. These pathways interact
with the molecular pathology
of ageing and induce neuronal
dysfunction and death, producing the
characteristic pathological features of
the condition.
We need to identify all the
significant genetic risk factors, and
place these molecules and their
variants in their pathways to enable
us to understand how the human
disease begins and develops.
To understand these pathways
and mechanisms requires the
establishment and integrated use of
a range of models.
The project
We aim to achieve a much fuller
picture of all the major genetic
factors that underlie Parkinson’s.
We will then identify and characterise
the biochemical pathways that these
genes determine, and explore their
role in the development of disease.
To dissect these mechanisms,
we have brought in expertise
from mitochondrial biology, cell
signalling and Drosophila biology
to complement our other model
systems.
In parallel we will study the
very earliest stages of the illness.
It is widely believed that only by
understanding these early phases
will we be able to modify the
disease course for the greatest
clinical impact. To aid this work,
we have harnessed the clinical
and biochemical resources of the
national Gaucher’s disease clinic.
This will help us to build cohorts of
individuals who are genetically at risk;
detailed studies of these individuals
will include imaging and biochemical
assessments.
Over the next five years, our plan
is to produce detailed knowledge of
the molecular pathways that lead to
Parkinson’s, and validated markers of
its evolution.
Principal investigators
University College London
(Institute of Neurology)
Nicholas Wood
John Hardy
Anthony Schapira
Co-investigators
University of Dundee
Dario Alessi (MRC Protein
Phosphorylation Unit)
University of Sheffield
Alex Whitworth (MRC Centre for
Developmental and Biomedical
Genetics)
University College London
Andrey Abramov (Institute of
Neurology)
Kailash Bhatia (Institute of Neurology)
J Mark Cooper (Institute of Neurology)
Michael Duchen (Dept of Physiology)
Derralyn Hughes (Royal Free)
Andrew Lees (Institute of Neurological
Studies)
Atul Mehta (Royal Free)
Tamas Revesz (Institute of Neurology)
Jan-Willem Taanman (MRC Centre for
Neuromuscular Diseases)
Tarek Yousry (MRC Centre for
Neuromuscular Diseases)
OTHER MRC AND WELLCOME TRUST GRANTS
IN NEURODEGENERATION RESEARCH
WELLCOME TRUST
MEDICAL RESEARCH COUNCIL
The Wellcome Trust has long funded research on
neurodegeneration at basic, clinical and translational
levels via a variety of funding mechanisms (e.g. Strategic
Awards, programme grants, project grants, and research
fellowships). Between 2000 and 2007 this amounted to a
total of £108 million. Examples demonstrating the breadth
of neurodegeneration research supported by the Trust
include:
The MRC supports a broad portfolio of neurodegeneration
research spanning basic, clinical and population research;
£150 million was committed to fund research in this
area between 2002 and 2006. It also has two dedicated
centres of excellence in neurodegeneration in London:
the MRC Centre for Neurodegeneration Research and the
MRC Prion Unit.
Strategic investments in neurodegeneration research
To generate novel RARa agonists for the treatment of
Alzheimer’s disease. This agonist has two mechanisms
of action – it regulates amyloid deposits in the brain and
plays a key role in the survival of neurons, and is a novel
target for the development of new treatments.
For more information on the the Seeding Drug Discovery
scheme, see www.wellcome.ac.uk/sdd.
Strategic Award (£5.9m, 2007)
Professors Linda Partridge and Dominic Withers and
Dr David Gems (University College London), and
Professor Janet Thornton (European Bioinformatics
Institute, Hinxton)
To explore the biological mechanisms that cause our
bodies to age and decay. Professor Partridge and
colleagues are looking at the cellular and biochemical
mechanisms of ageing in fruit flies, nematode worms
and mice, with a particular focus on the role of insulin
signalling. They are also exploring how their findings in
the animal models relate to the human ageing process, in
particular neurodegenerative diseases.
Project grant (£1.3m, 2007)
Professor Julie Williams (Cardiff University)
To undertake a genome-wide association scan of the entire
human genome in search of the genes that predispose
people to, or protect them from, Alzheimer’s disease. DNA
samples are being taken from 14 000 people – 6000 with
late-onset Alzheimer’s and 8000 healthy ‘control’ samples
from the UK and USA – and are being analysed to identify
common genetic variations that increase the risk of the
disease. This is the largest Alzheimer’s gene study to date.
For more information on Neuroscience and Mental Health
at the Wellcome Trust, contact: nmh@wellcome.ac.uk.
Further details can also be found on the Trust’s website:
www.wellcome.ac.uk/funding
£10m has recently been invested in three new research
centres encompassing neurodegeneration research,
all made in partnership with UK universities. The MRC
Centre for Neuropsychiatric Genetics and Genomics in
Cardiff was awarded in 2009, while two centres were
awarded in 2008 under the cross-Research Council
initiative on Lifelong Health and Wellbeing – the Centre
in Cognitive Ageing and Cognitive Epidemiology in
Edinburgh (www.ccace.ed.ac.uk) and the Centre for
Brain Ageing and Vitality in Newcastle (www.ncl.ac.uk/
iah/research/centres/cbav/).
UK Brain Banks Network
The MRC is spearheading a new strategy to link the UK’s
existing human brain banks into a national network to
ensure that researchers can get better access to highquality tissue and, ultimately, to speed the process of
turning lab discoveries into treatments. Professor James
Ironside has been appointed as Director of the Network.
More details of the UK Brain Banks Network can be found
at www.mrc.ac.uk/Ourresearch/Resourceservices/
UKbrainbanksnetwork/.
PET imaging for brain research
Positron emission tomography (PET) is a key tool
for development of new therapeutic approaches for
neurodegenerative and psychiatric disorders. The MRC
is leading an initiative to facilitate UK PET imaging in
brain research.
Further details on the PET initiative and strategy can be
found at www.mrc.ac.uk/Fundingopportunities/Calls/PET/.
Q-L Ying and A Smith
Seeding Drug Discovery award (£3m, 2008)
Dr Jonathan Corcoran and Professor Malcolm Maden
(King’s College London)