Neurodegenerative Diseases Initiative Funding Brochure

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: [email protected]. 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)