The genetics of motor neuron degenerative diseases
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
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.
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.
Publications

Chiò A
(2009)
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.
in Human molecular genetics

Garrett CA
(2014)
DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy.
in Brain : a journal of neurology

Hithersay R
(2019)
Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years.
in JAMA neurology

Ingram CJ
(2012)
Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis.
in Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases

Kasperaviciute D
(2007)
Large-scale pathways-based association study in amyotrophic lateral sclerosis.
in Brain : a journal of neurology

Need AC
(2009)
A genome-wide investigation of SNPs and CNVs in schizophrenia.
in PLoS genetics

Rishal I
(2012)
A motor-driven mechanism for cell-length sensing.
in Cell reports

Schiavo G
(2013)
Cytoplasmic dynein heavy chain: the servant of many masters.
in Trends in neurosciences

Startin CM
(2019)
Cognitive markers of preclinical and prodromal Alzheimer's disease in Down syndrome.
in Alzheimer's & dementia : the journal of the Alzheimer's Association

Wills AM
(2009)
A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.
in Neurology
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 |