The genetics of motor neuron degenerative diseases

Lead Research Organisation: University College London
Department Name: UNLISTED


EF considers the public dissemination of science to be paramount, especially for a subject such as genetics. She has lectured to school teachers on behalf of the Wellcome Trust, talked on television and radio, and given lectures to children in schools and at the Royal Institution, and has talked at a number of other venues for the lay public including the Science Museum.

Technical Summary

Motor neuron degeneration diseases (MNDs) are lethal disorders that affect young and old, and are relatively common. For example, spinal muscular atrophy is the most common genetic killer of children, worldwide; another MND, amyotrophic lateral sclerosis (ALS) has a lifetime risk of 1 in 1000. Currently ~1 in 500 death certificates in England and Wales give cause of death as forms of MND. The MNDs progress from paralysis to death, and are all untreatable and incurable. ALS strikes typically in 40s and 50s and death and complete paralysis follow usually within 3 years of diagnosis. Generally intelligence remains in tact. So far only one gene, SOD1, has been found that is causal for ~10% of adult onset familial ALS, however 80% of ALS is sporadic and of unknown aetiology, although clearly other genes are involved. Thus ~98% of ALS remains of unknown cause, and the toxic gain of function of mutant SOD1 also remains unknown.

Through working with mouse models, including SOD1 transgenics that model ALS, we have identified the dynein-dynactin complex as involved in specific motor neuron degeneration. Within the last 6 months we have unexpected new data DIRECTLY LINKING MUTANT (ALS)SOD1 WITH THE DYNEIN-DYNACTIN PATHWAY. Therefore we believe the genes in this retrograde transport motor complex are candidates for association with ALS, and potentially other MNDs (and other forms of neurodegeneration). To sequence the genes in this pathway would be prohibitively expensive, and there is no viable platform available yet for whole genome scanning studies; therefore we wish to harness the results of the world-wide Haplotype Mapping project, and assess the individual dynein-dynactin pathway genes for association with disease. Our approach is to identify a subset of SNPs within each gene, termed haplotype tagging SNPs, that are sufficient to represent all of the common variants in the gene. We will then assay these SNPs in a large set of well-defined patient samples, and look for association between disease status and gene haplotype.

We have an established track record in haplotype mapping studies, and in ALS research, and an excellent patient and control resource for this study. We have some pilot data for this project and now wish to apply for funding to ramp up to a full scale study working efficiently and cost effectively with the Core Haplotype Mapping Group headed by Professor David Goldstein.


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Description MRC
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Description MMON 
Organisation MRC Harwell
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with the Mouse Models of Neurodegeneration lab at MRC Harwell, analysis of homozygous and heterozygous mice
Collaborator Contribution Breeding, inbreeding onto another background, and phenotypic analysis of homozygous and heterozygous mice.
Impact Inbred mice on different backgrounds. Cohorts of mice of different ages, sex-matched with littermate controls, wildtype, heterozygous, homozygous, for phenotypic analysis. Analysis of different phenotypes ranging from behavioural through to physiological.
Start Year 2017
Description Mouse dynein mutant new 
Organisation Weizmann Institute of Science
Country Israel 
Sector Academic/University 
PI Contribution requesting a novel dynein mutant mouse to be made that was then sent on to our collaborators at the Weizmann
Collaborator Contribution Phenotypic work up of the mouse
Impact Pending
Start Year 2014