Mutations in the Vacuolar protein sorting 35 (VPS35) gene have been linked to familial Parkinson’s disease (PD), PARK17. VPS35 is a key component of the retromer complex, which plays a central role in endosomal trafficking. However, whether and how VPS35 deficiency or mutation contributes to PD pathogenesis remain unclear. Here, we analyzed human induced pluripotent stem cell (iPSC)-derived neurons from PD patients with the VPS35 D620N mutation and addressed relevant disease mechanisms. In the disease group, dopaminergic (DA) neurons underwent extensive apoptotic cell death. The movement of Rab5a- or Rab7a-positive endosomes was slower, and the endosome fission and fusion frequencies were lower in the PD group than in the healthy control group. Interestingly, vesicles positive for cation-independent mannose 6-phosphate receptor transported by retromers were abnormally localized in glial cells derived from patient iPSCs. Furthermore, we found α-synuclein accumulation in TH positive DA neurons. Our results demonstrate the induction of cell death, endosomal dysfunction and α -synuclein accumulation in neural cells of the PD group. PARK17 patient-derived iPSCs provide an excellent experimental tool for understanding the pathophysiology underlying PD.

中文翻译：

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VPS35 D620N帕金森氏病患者的iPSC衍生神经细胞的内体功能障碍

Vacuolar蛋白质分选35（VPS35）基因中的突变与家族性帕金森氏病（PD）PARK17相关。VPS35是逆转录复合物的关键组成部分，在内体运输中起着核心作用。然而，尚不清楚VPS35缺陷或突变是否以及如何导致PD发病。在这里，我们分析了具有VPS35 D620N突变的PD患者的人诱导多能干细胞（iPSC）衍生神经元，并探讨了相关的疾病机制。在疾病组中，多巴胺能（DA）神经元经历了广泛的凋亡细胞死亡。PD组的Rab5a阳性或Rab7a阳性核内体的运动较慢，并且核内体的分裂和融合频率低于健康对照组。有趣的是 逆转录酶转运的不依赖阳离子的甘露糖6-磷酸受体阳性的囊泡异常定位在源自患者iPSC的神经胶质细胞中。此外，我们发现α-突触核蛋白在TH阳性DA神经元中蓄积。我们的结果证明了PD组神经细胞中细胞死亡，内体功能障碍和α-突触核蛋白积聚的诱导。PARK17患者衍生的iPSC为了解PD的病理生理学提供了出色的实验工具。