Loss-of-function mutations in VPS13C are linked to early-onset Parkinson’s disease (PD). While VPS13C has been previously studied in non-neuronal cells, the neuronal role of VPS13C in disease-relevant human dopaminergic neurons has not been elucidated. Using live-cell microscopy, we investigated the role of VPS13C in regulating lysosomal dynamics and function in human iPSC-derived dopaminergic neurons. Loss of VPS13C in dopaminergic neurons disrupts lysosomal morphology and dynamics with increased inter-lysosomal contacts, leading to impaired lysosomal motility and cellular distribution, as well as defective lysosomal hydrolytic activity and acidification. We identified Rab10 as a phospho-dependent interactor of VPS13C on lysosomes and observed a decreased phospho-Rab10-mediated lysosomal stress response upon loss of VPS13C. These findings highlight an important role of VPS13C in regulating lysosomal homeostasis in human dopaminergic neurons and suggest that disruptions in Rab10-mediated lysosomal stress response contribute to disease pathogenesis in VPS13C-linked PD.

中文翻译：

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VPS13C 调节人多巴胺能神经元中磷酸 Rab10 介导的溶酶体功能


VPS13C 的功能丧失突变与早发性帕金森病 (PD) 相关。虽然之前已在非神经元细胞中研究了 VPS13C，但 VPS13C 在疾病相关的人类多巴胺能神经元中的神经元作用尚未阐明。使用活细胞显微镜，我们研究了 VPS13C 在调节人 iPSC 衍生的多巴胺能神经元溶酶体动力学和功能中的作用。多巴胺能神经元中 VPS13C 的缺失会破坏溶酶体的形态和动力学，并增加溶酶体间的接触，导致溶酶体运动和细胞分布受损，以及溶酶体水解活性和酸化缺陷。我们确定 Rab10 是溶酶体上 VPS13C 的磷酸依赖性相互作用因子，并观察到 ​​VPS13C 丢失后磷酸 Rab10 介导的溶酶体应激反应降低。这些发现强调了 VPS13C 在调节人类多巴胺能神经元溶酶体稳态中的重要作用，并表明 Rab10 介导的溶酶体应激反应的破坏有助于 VPS13C 相关 PD 的疾病发病机制。