Dissecting the processes of motor neuron disease

All four applicants consider the public dissemination of science at all levels, to be paramount, especially for subjects such as genetics and neurobiology. They have all lectured to non-specialists ranging from CEOs of leading utility companies to local school children, and at the Royal Institution to the Science Museum. In addition, for example, EF was a BA Media Fellow and worked for 8 weeks in the BBC World Service, conveying science to an international audience, and still has strong ties to the Association of British Science Writers including judging their 2003 and 2004 ABSW awards. All groups also regularly give talks to the lay public in Patients and Carers groups.

This Research Grant application is for a 4-year focussed mutagenesis project to create a resource for functionally dissecting the mechanism of mutant SOD1 action and neurodegeneration.

Motor neuron diseases (MNDs) are relatively common (1 in 500 death certificates is issued for some form of MND) and can strike at any age ? spinal muscular atrophy is the biggest single genetic killer of children world-wide, whereas amyotrophic lateral sclerosis is a disease of mid-life (40s, 50s). These disease progress inexorably to paralysis and death and we have no treatments that significantly improve quality of life or lifespan of sufferers. Clearly MNDs have a genetic component and are genetically heterogeneous, however only one major effect causative gene, SOD1 has been found (in 1993) and we still have no idea as to its toxic gain of function. Thus there are 2 key issues in MND research, which are also relevant to basic neurobiology studies of motor neuron function:
1. what is the toxic gain of function of mutant SOD1?
2. what other genes and hence pathways are associated with MN death and dysfunction?

We will attack these questions in an innovative Program that capitalises on the unique combination of the genetics and phenotyping skills of our groups, our existing collaborations with a wide range of scientists and clinicians, and access to one of the world?s premier mouse resources at MRC Harwell. We will set up a SENSITISED-SCREEN to look for genes/pathways that specifically affect the toxic gain of function of mutant SOD1. We will use the resulting set of new mutations as a future resource for us and the MND community for detailed phenotypic and genetic analysis to dissect molecular processes leading us to important cell biological pathways involved in the mutant SOD1 gain of function, ultimately for translation into therapeutic targets.