Genetic characterization of atypical parkinsonism

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

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 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 to generate foundational genomic data focused on understanding these disabling diseases. We created the largest genomic resource of Lewy body dementia and mapped five common risk loci. We defined pathways associated with this disease and illustrated molecular overlaps with Parkinson's disease and Alzheimer's disease. We found enrichment of rare mutations in the genes GBA and GRN in this patient population. Further, we identified subtypes of Lewy body dementia that are hallmarked by the high-risk alleles at the APOE and GBA loci. Our ongoing efforts focus on increasing the number of participants to explain the missing heritability of Lewy body dementia. We are using similar efforts in multiple system atrophy to identify risk loci that are essential drivers in the pathogenesis of this disease. We will continue to apply modern genomic techniques to dissect the genetic risk factors and pathways underlying atypical parkinsonism syndromes. The resulting molecular insights will act as a springboard for future systems biology investigations and translational research efforts.