Parkinson's disease (PD) is a complex and highly variable neurodegenerative disease. Familial PD is caused by mutations in several genes with diverse and mostly unknown functions. It is unclear how dysregulation of these genes results in the relatively selective death of nigral dopaminergic neurons (DNs). To address this question, we modeled PD by knocking out the PD genes PARKIN (PRKN), DJ-1 (PARK7), and ATP13A2 (PARK9) in independent isogenic human pluripotent stem cell (hPSC) lines. We found increased levels of oxidative stress in all PD lines. Increased death of DNs upon differentiation was found only in the PARKIN knockout line. Using quantitative proteomics, we observed dysregulation of mitochondrial and lysosomal function in all of the lines, as well as common and distinct molecular defects caused by the different PD genes. Our results suggest that precise delineation of PD subtypes will require evaluation of molecular and clinical data.

帕金森氏病（PD）是一种复杂且高度可变的神经退行性疾病。家族性PD是由几种具有多种功能且大多数未知功能的基因突变引起的。尚不清楚这些基因的失调如何导致相对选择性的黑质多巴胺能神经元（DNs）死亡。为了解决这个问题，我们通过在独立的等基因人类多能干细胞（hPSC）系中剔除PD基因PARKIN（PRKN），DJ-1（PARK7）和ATP13A2（PARK9）来建模PD 。我们发现所有PD品系中的氧化应激水平均升高。仅在PARKIN中发现分化后DN的死亡增加淘汰赛线。使用定量蛋白质组学，我们观察到了所有品系中线粒体和溶酶体功能的失调，以及由不同的PD基因引起的常见和独特的分子缺陷。我们的结果表明，PD亚型的精确描述将需要评估分子和临床数据。