Genetics of Early Onset Parkinsons Disease: Mitochondrial Drivers of PD Pathogenesis

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Parkinsons disease (PD) represents a substantial and growing public health burden, affecting 680,000 people in the US. The cause of PD is monogenic in roughly 10% of cases, and identified genes point to targetable pathways for drug development. The most common monogenic cause of Early Onset PD (EOPD, onset 50) are loss of function (LOF) mutations in Parkin and PINK1, which affect thousands of individuals in the US. These genes not only share clinical features, but, as our work established, function in a common biological pathway to target dysfunctional mitochondria for autophagy. Interestingly, autosomal dominant mutations in CHCHD2 and its paralog CHCHD10, mitochondrial proteins of unknown function, were recently identified as also causing EOPDunderscoring a key clinical-biological correlation between EOPD and mitochondrial dysfunction. Despite substantial progress in EOPD molecular and functional genetics over the last 20 years, however, there remain a number of challenges for translating genetic discovery to targeted therapies for PD. The overall goal of our program is to characterize the genomic architecture, clinical phenotype, and functional genetics of EOPD to identify mitochondrial drivers of PD pathogenesis and foster targeted therapies for PD. To that end, we propose three complementary aims that draw on strengths of the intramural program and my perspective as a cell biologist and neurologist.