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

帕金森病（PD）是一种巨大且不断增长的公共卫生负担，影响了美国68万人。PD的原因在大约10%的病例中是单基因的，并且鉴定的基因指向药物开发的靶向途径。早发性PD（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，这影响了美国成千上万的个体。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发挥作用，靶向功能失调的线粒体进行自噬。有趣的是，CHCHD2及其parasitic CHCHD10的常染色体显性突变，线粒体蛋白的未知功能，最近被确定为也导致EOPD强调EOPD和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年中，在EOPD分子和功能遗传学方面取得了实质性进展，但是，将遗传发现转化为PD的靶向治疗仍然存在许多挑战。 我们项目的总体目标是表征EOPD的基因组结构、临床表型和功能遗传学，以确定PD发病机制的线粒体驱动因素，并促进PD的靶向治疗。为此，我们提出了三个互补的目标，利用校内计划的优势和我作为细胞生物学家和神经学家的观点。

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.