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Neurodegenerative Diseases Initiative Funding Brochure
Neurodegenerative Diseases Initiative Funding Brochure
Neurodegenerative Diseases Initiative Funding Brochure
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 Wellcome Trust Medical Research Council
with new opportunities and new challenges. An opportunity to respect Neurodegenerative diseases, such To solve the complex puzzles posed
and harness the contributions that older people make to society in terms as Alzheimer’s, Parkinson’s and by neurodegenerative diseases,
of experience, skills and wisdom; and the challenge of tackling the health motor neurone diseases, cause a investment in innovative research
problems that they face. Among these are age-associated neurodegenerative great deal of human suffering and is a crucial priority for the Medical
diseases that insidiously affect the body and brain, and which can so radically place considerable burden on our Research Council (MRC). This
affect the quality of their lives. health services. Better understanding initiative will help to deliver the tools
of what causes these conditions to achieve earlier diagnosis and
It is fitting that we should devote a significant effort in UK science to securing and ever earlier identification of better treatment and prevention
a better understanding of these disorders. It has been my privilege to chair the their incipient onset would be strategies required to improve the
joint Wellcome Trust–Medical Research Council Neurodegenerative Diseases immensely beneficial. New advances lives of the many people affected by
Initiative Funding Committee, which selected the three excellent awards in biomedical science, ranging from neurodegenerative conditions.
highlighted here, in the face of tough competition. We were presented with epidemiological through to molecular
a range of exciting research proposals that sought to tackle the causes and and genetic studies – make this an The awards funded under this joint
neurobiology of a number of neurodegenerative diseases. exceptionally timely moment to have initiative will add further momentum
a focused initiative. The Wellcome to the MRC’s existing investments
Our aim was to choose teams of researchers with a clear vision on how to Trust is delighted to be collaborating in neurodegeneration research.
tackle these neurodegenerative conditions; who would utilise their technical with the Medical Research Council Furthermore, these investments
skills creatively to make real progress in understanding the causes and in providing major funding for this will provide opportunities for further
pathway to disease; moreover, whose work would lead to the eventual important area of research. collaboration across Europe, where
development of novel diagnostic tools and therapeutics. These benefits will the MRC has had a leading role in
not materialise overnight – for the scientific challenges are considerable – Sir Mark Walport developing the new European Union
but these major awards will change the research landscape in which these Director, Wellcome Trust initiative in neurodegeneration and
disorders are being addressed. 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.
neurodegenerative disorders beta) or tau genes appear to play a activated by the accumulation of Research (CIMR), University of
Cambridge
crucial role in this process in some amyloid beta and tau, and that
Peter St George-Hyslop
cases. This observation has led to the ultimately lead to the death of
Mechanisms of neurotoxicity of amyloid aggregates conclusion that events that cause the brain cells. Co-investigators
accumulation of amyloid beta and tau We aim to determine why and University of Cambridge
activate a set of downstream cellular how both amyloid beta and tau Timothy Bussey (Dept of Experimental
Psychology)
signalling and metabolic events that accumulate in the brains of people
Damian Crowther (Dept of Genetics)
ultimately kill nerve cells. with Alzheimer’s disease, and why Christopher Dobson (Dept of
Summary 450 000 of cases this is caused However, attempts using the normal mechanisms for removing Chemistry)
We will use novel methods from by Alzheimer’s disease) and this conventional tools to understand aggregated proteins from brain cells Giorgio Favrin (Dept of Chemistry)
physics, chemistry and biology to number will double to 1.4 million by why brain cells are killed by the become overwhelmed. We will also Clemens Kaminski (Dept of Chemical
discover the molecular mechanisms 2037. These diseases cost the UK accumulation of these proteins have search for drug-like molecules that Engineering & Biotechnology)
David Klenerman (Dept of Chemistry)
that result in the death of brain cells economy about £17 billion, which yielded confusing and conflicting stabilise aggregation-prone proteins
David Lomas (CIMR)
in Alzheimer’s disease and related will rise to at least £50bn by 2037. results. We still do not know what such as tau as potential therapies for Cahir O’Kane (Dept of Genetics)
neurodegenerative disorders with Worldwide, 37m people are affected types of aggregates formed by these these diseases. Stephen Oliver (Dept of Biochemistry)
accumulation of amyloid beta and/ by these diseases – they are the proteins are toxic to brain cells, nor The knowledge and tools we David Rubinsztein (CIMR)
or tau. This information will allow the fourth leading cause of death among do we know how they disturb the generate will provide a rational Lisa Saskida (Dept of Experimental
creation of accurate and sensitive adults in industrialised societies, metabolic and signalling machinery basis for the future development of Psychology)
Gergely Toth (Dept of Chemistry)
diagnostic tests and new ways to and are becoming an increasingly inside nerve cells. diagnostic profiles that could enable
Michele Vendruscolo (Dept of
treat these diseases. significant healthcare problem in Recently, we have developed doctors to detect the disease in its Chemistry)
developing countries. powerful biophysical and chemical earliest stages, before irreversible
damage is done to the brain, and to University of Bristol
The problem Although we know that several approaches that will allow us to
Kei Cho
Alzheimer’s disease and related genes and environmental effects can visualise individual aggregate personalise and monitor treatment Graham Collingridge
disorders are increasingly common cause Alzheimer’s disease, we do species, to watch which types of programmes for individual patients,
degenerative disorders of the brain not know why or how they lead to aggregates bind to cells, and to based on the cellular networks that Max-Planck-Unit for Structural
Molecular Biology, Germany
that occur in mid-to-late adult life. the death of nerve cells in the brain. identify the downstream pathways have been disrupted.
Eckhard Mandelkow
They cause impairments in memory The paucity of knowledge about the that they activate. Similarly, we have Knowledge of these pathways will Eva-Maria Mandelkow
and intellectual function, and lead to molecular mechanics of these diseases developed a variety of cellular and also provide potential targets for the
University of Toronto, Canada
death within 10–15 years of diagnosis. has hampered the development of whole-organism models of these development of new therapies to repair
Paul Fraser
In the UK, 700 000 people sensitive and accurate tests and diseases as well as computational these pathways, thereby preventing or Ekaterina Rogaeva
Peter St George-Hyslop, Principal Investigator.
suffer from dementia (in around effective treatments. and systems biology tools that will even reversing the disease. Gerold Schmitt-Ulms
Funding from the Wellcome Trust–MRC initiative
will allow us to turn ideas into experiments. Christopher Shaw, Principal Investigator.
The questions
Induced pluripotent stem cells in a patient with the M337V mutation in the TARDBP gene. Agnes Nishimura
For the past 15 years, we have
known that mutations in the MAPT
Motor neurones synapsing with muscles in Drosophila development. Dr Andrea H Brand
gene cause FTD with features of
Parkinsonism, and that mutations To investigate the roles of The team
in the SOD1 gene cause MND. PGRN, TARDBP and FUS, we will
frontotemporal dementia has been discovered that the RNA- (to test a loss of function) or have Centre for Neurodegeneration
processing proteins TDP-43 and mutated genes (to test a toxic gain Research)
Christopher Shaw
FUS are deposited in nerve cells in of function). We will conduct similar
The role of RNA-processing proteins in neurodegeneration the majority of MND and FTD cases, experiments in the fruit fly (which Co-investigators
proving that these two diseases are will allow us to map out interacting University of California,
linked through their pathology. pathways), zebrafish (which will San Diego
Members of our consortium have allow us to rapidly screen drugs) and Don Cleveland (Ludwig Institute
for Cancer Research)
recently discovered mutations in the mouse (which, having a mammalian
Summary The problem weakness that begins in one hand genes PGRN, TARDBP and FUS in nervous system similar to humans, University of Cambridge
Recent research on motor neurone FTD is the second most common or foot but rapidly spreads to other families with strongly inherited forms should give us the closest disease Jernej Ule (MRC Laboratory
for Molecular Biology)
disease (MND) and frontotemporal cause of dementia in the under- parts of the body, leaving people of FTD and MND. The challenge model). These models can also
dementia (FTD) has shown that 65s, and accounts for 10 per cent paralysed, unable to walk, talk and now is to understand how these be used to discover drugs that University of Dundee
RNA-processing proteins called of all cases of dementia. It causes eat. Patients feel hopeless and mutations cause disease. We do not may slow down or even arrest the John Rouse (MRC Protein
Phosphorylation Unit)
TDP-43 and FUS are deposited progressive problems with personality, helpless. MND is the single most know whether they cause disease disease process in humans.
in degenerating nerve cells. Rare behaviour and language, and common reason that people seek due to a loss of the protein function We also aim to look at the King’s College London
mutations in three genes – PGRN, therefore differs from Alzheimer’s euthanasia. There are clear genetic or due to a new toxic property normal function of the proteins Jean-Marc Gallo (MRC Centre for
Neurodegeneration Research)
TARDBP and FUS – cause a form of disease, in which memory problems links in 10 per cent of cases, but the acquired by the mutant protein. produced by these genes and
Noel Buckley (Centre for the Cellular
these diseases. These discoveries predominate. The change in behaviour genes linked to MND account for characterise their DNA- and Basis of Behaviour)
allow us to make cellular and animal and personality is particularly hard on only 5 per cent of all cases. The project RNA-binding properties, and Corrine Houart (MRC Centre for
models that reproduce key aspects families. In 40 per cent of cases, other There is no treatment for either We plan to develop cellular and the functional effects of protein Developmental Neurobiology)
of the human disorders, allowing family members are affected and there FTD or MND that can significantly animal models that will allow us to phosphorylation. Lastly we will
University of Manchester
us to explore fundamental disease is a strong genetic basis. improve survival. All treatment understand what makes nerve cells attempt to repair the defective Stuart Pickering-Brown (Clinical
mechanisms and identify new MND kills 1200 people in the is directed towards controlling degenerate and to explore how we genes using gene therapy in the Neurosciences)
therapeutic targets. UK every year. It causes muscular symptoms, and to practical and might reverse this process. cellular and animal models. David Mann (Neuroscience Centre)
Rows of different individuals’ DNA sequences aligned at the same position
in the genome, showing single nucleotide polymorphisms (SNPs).
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
Co-investigators
Summary UK, this means there are over 100 000 also focus on developing our disease begins and develops. In parallel we will study the University of Dundee
The cause of Parkinson’s disease people with the disease: with the understanding of the very early To understand these pathways very earliest stages of the illness. Dario Alessi (MRC Protein
Phosphorylation Unit)
is unknown, although it is clear that ageing population this number will symptoms or warnings of the illness. and mechanisms requires the It is widely believed that only by
it is a disease of ageing and there increase. The annual cost in nursing- establishment and integrated use of understanding these early phases University of Sheffield
are now some established genetic home care for Parkinson’s disease The questions a range of models. will we be able to modify the Alex Whitworth (MRC Centre for
Developmental and Biomedical
risk factors. To understand how alone in the UK is estimated to be We hypothesise that there are disease course for the greatest
Genetics)
these factors combine, we aim to about £600–800 million. multiple causes of Parkinson’s, which The project clinical impact. To aid this work,
dissect and understand the genetic Despite tremendous progress in result in a very small number of We aim to achieve a much fuller we have harnessed the clinical University College London
Andrey Abramov (Institute of
architecture of Parkinson’s disease, the identification of genes associated separate but converging biochemical picture of all the major genetic and biochemical resources of the
Neurology)
to identify and characterise the with Parkinson’s and related pathways. These pathways interact factors that underlie Parkinson’s. national Gaucher’s disease clinic. Kailash Bhatia (Institute of Neurology)
biochemical pathways involved, and disorders over the last decade, we with the molecular pathology We will then identify and characterise This will help us to build cohorts of J Mark Cooper (Institute of Neurology)
to take lessons from the biology still have only outline and sketchy of ageing and induce neuronal the biochemical pathways that these individuals who are genetically at risk; Michael Duchen (Dept of Physiology)
of people at risk of the disease to information about the molecular dysfunction and death, producing the genes determine, and explore their detailed studies of these individuals Derralyn Hughes (Royal Free)
understand its very earliest stages. pathways involved, and their characteristic pathological features of role in the development of disease. will include imaging and biochemical Andrew Lees (Institute of Neurological
Studies)
constituents and their interactions. the condition. To dissect these mechanisms, assessments.
Atul Mehta (Royal Free)
The problem Finally, if we are really to We need to identify all the we have brought in expertise Over the next five years, our plan Tamas Revesz (Institute of Neurology)
Parkinson’s disease is a common understand the pathway to human significant genetic risk factors, and from mitochondrial biology, cell is to produce detailed knowledge of Jan-Willem Taanman (MRC Centre for
neurodegenerative disease that disease, and if we are to influence place these molecules and their signalling and Drosophila biology the molecular pathways that lead to Neuromuscular Diseases)
afflicts more than 2 per cent of its progression, we need to examine variants in their pathways to enable to complement our other model Parkinson’s, and validated markers of Tarek Yousry (MRC Centre for
people aged over 75 years. In the the earliest phase. Thus we will us to understand how the human systems. its evolution. Neuromuscular Diseases)
OTHER MRC AND WELLCOME TRUST GRANTS
IN NEURODEGENERATION RESEARCH