Genetics of Early Onset Parkinson's Disease: Mitochondrial Drivers of PD Pathogenesis

帕金森病（PD）是一个巨大且不断增长的公共卫生负担，在美国影响着68万人。在大约10%的病例中，帕金森病的病因是单基因的，已确定的基因指向了药物开发的可靶向途径。早发性帕金森病（EOPD，发病50）最常见的单基因原因是Parkin和PINK1的功能丧失（LOF）突变，在美国影响了数千人。这些基因不仅具有共同的临床特征，而且正如我们的工作所建立的那样，它们在一个共同的生物学途径中起作用，以靶定功能失调的线粒体进行自噬。有趣的是，CHCHD2及其平行体CHCHD10（功能未知的线粒体蛋白）的常染色体显性突变最近被发现也可引起EOPD，这强调了EOPD与线粒体功能障碍之间的关键临床生物学相关性。尽管在过去的20年里，EOPD分子和功能遗传学取得了实质性的进展，但是，将基因发现转化为PD的靶向治疗仍然存在许多挑战。

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.