Etiological Linkage of DNA Damage/Repair Deficiency in Neurodegenerative Diseases
Description: PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal motor neuron degenerative disease, for which no effective treatment is available even for slowing down the disease progression. Multiple, complex pathologies have been implicated, including the RNA/DNA binding protein TDP-43's nucleus cytoplasm redistribution in a majority of both sporadic and inherited cases; however the molecular mechanisms of its pathology and/or physiological consequence(s) leading to neuronal death/dysfunction are still unknown. The project will establish that TDP-43 is a key component of DNA double strand break (DSB) machinery in neurons of healthy individuals and its loss of nuclear functions in ALS and other TDP-43-associated neurodegenerative diseases which include about 40% of Alzheimer's and Parkinson's disease affected patients, leads to deficient DSB repair. The resulting accumulation of lethal DSBs promotes neuronal toxicity and death. Thus this innovative grant proposal, based on strong preliminary data, will examine previously unexplored area of ALS research that would lead to a major paradigm shift in our understanding of the molecular pathogenesis of not only ALS, but also other TDP-43-associated neurodegenerative diseases; and could open up new avenues of therapeutic interventions.
Funding type: research
Funder scheme: R01
Start date: 2015-07-01
End date: 2022-06-30
Investigator: MURALIDHAR L HEGDE
Institution: METHODIST HOSPITAL RESEARCH INSTITUTE
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 71
Funder award ID: R01NS088645
OpenAlex ID: G1522902277