Genetic characterization of atypical parkinsonism

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Understanding the molecular pathogenesis of atypical parkinsonism is critical for identifying targets that could be translated into therapies. Over the last two decades, we have learned that the genetic contributions to these age-related neurodegenerative syndromes can be complex, involving both common and rare risk variants. Our mission is to define the genetic architectures of atypical parkinsonism syndrome using modern genomic tools. We aim to leverage this knowledge to understand the broader neurodegenerative disease spectrum. Toward this end, we established the International Lewy Body Dementia Genomics Consortium and the International Multiple System Atrophy Genomics Consortium. We generated foundational genomic data focused on understanding these disabling diseases. In the last year, we performed genome-wide structural variant mapping based on short-read genome sequence data of 9,000 people. We discovered a common deletion in the gene TPCN1 as a novel risk factor for Lewy body dementia. We also identified several rare pathogenic structural variants and generated an interactive app that allows researchers to query these data for new insights into dementia syndromes. Further, by combining our genomic data with neuropathological information, we defined distinct subtypes of LBD and showed that the GBA drives one form of disease, whereas the APOE 4 risk allele drives the other. In summary, our work provides critical insights into the molecular mechanisms underlying these understudied neurodegenerative conditions. The knowledge garnered from this initiative will improve disease modeling and the development of targeted therapeutics.