The role of RNA-processing proteins in neurodegeneration
To find out more about the consortium, please visit their website at http://neurodegen.iop.kcl.ac.uk/
In the video below, Professor Chris Shaw explains how motor neurone disease affects those with the condition. He also discusses the recent breakthroughs into the disease made by his team of researchers and how the new consortium will build upon these discoveries (running time: 2 min 53 s).
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The problem
Frontotemporal dementia (FTD) is the second most common cause of dementia in the under-65s, 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.
Motor neurone disease (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 emotional support of the patient and their family. Both disorders are relentlessly progressive and are fatal within three to five years on average.
The questions
For the past 15 years, it has been 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 RNA processing 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 the consortium, led by Professor Shaw, 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. It is not known 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 research programme
The consortium plans to develop cellular and animal models that will allow it to understand what makes nerve cells degenerate and to explore how this process might be reversed.
To investigate the roles of PGRN, TARDBP and FUS, the consortium 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). It will conduct similar experiments in the fruit fly (which will allow it to map out interacting pathways), zebrafish (which will allow it to rapidly screen drugs) and mouse (which, having a mammalian nervous system similar to humans, should giveit 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.
The consortium also aims 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 it 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)
Image: Motor neurones synapsing with muscles in Drosophila development. Dr Andrea H Brand
