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Abstract：
Parkinson\'s disease (PD) is one of the most common neuro-degenerative diseases characterized by α-synuclein accumulation and degeneration of dopaminergic neurons. Employing genome-wide sequencing, we identified a polymorphic USP8 allele (USP8D442G) significantly enriched in Chinese PD patients. To test the involvement of this polymorphism in PD pathogenesis, we derived dopaminergic neurons (DAn) from human-induced pluripotent stem cells (hiPSCs) reprogrammed from fibroblasts of PD patients harboring USP8D442G allele and their healthy siblings. In addition, we knock-in D442G polymorphic site into the endogenous USP8 gene of human embryonic stem cells (hESCs) and derived DAn from these knock-in hESCs to explore their cellular phenotypes and molecular mechanism. We found that expression of USP8D442G in DAn induces the accumulation and abnormal subcellular localization of α-Synuclein (α-Syn). Mechanistically, we demonstrate that D442G polymorphism enhances the interaction between α-Syn and USP8 and thus increases the K63-specific deubiquitination and stability of α-Syn . We discover a pathogenic polymorphism for PD that represent a promising therapeutic and diagnostic target for PD.
摘要：
帕金森病(PD)是一种以α-突触核蛋白积累和多巴胺能神经元变性为特征的常见神经退行性疾病。采用全基因组测序，我们在中国PD患者中发现了一个显著富集的多态性USP8等位基因(USP8D442G).为了测试这种多态性在PD发病机制中的参与，我们从具有USP8D442G等位基因的PD患者及其健康同胞的成纤维细胞重编程的人诱导多能干细胞（hiPSCs）中衍生出多巴胺能神经元（DAn）。此外,我们将D442G多态性位点敲入人胚胎干细胞（hESCs）的内源性USP8基因，并从这些敲入的hESCs中衍生DAn，以探讨其细胞表型和分子机制。我们发现USP8D442G在DAn中的表达诱导α-突触核蛋白（α-Syn）的积累和异常的亚细胞定位。机械上,我们证明D442G多态性增强了α-Syn和USP8之间的相互作用，从而增加了K63特异性去泛素化和α-Syn的稳定性。我们发现PD的致病性多态性代表了PD的有希望的治疗和诊断靶标。
