Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Biochemistry III/Faculty of Chemistry, Bielefeld University, Bielefeld, Germany.
J Cell Biol. 2024 May 6;223(5). doi: 10.1083/jcb.202304042. Epub 2024 Feb 15.
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.
VPS13C 的功能丧失突变与早发性帕金森病（PD）有关。虽然 VPS13C 已在非神经元细胞中进行了研究，但 VPS13C 在与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。我们使用活细胞显微镜研究了 VPS13C 在调节人诱导多能干细胞衍生的多巴胺能神经元中的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，增加溶酶体之间的接触，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 VPS13C 在溶酶体上的磷酸依赖性相互作用蛋白，并观察到 VPS13C 缺失时磷酸化 Rab10 介导的溶酶体应激反应减少。这些发现强调了 VPS13C 在调节人类多巴胺能神经元溶酶体动态平衡中的重要作用，并表明 Rab10 介导的溶酶体应激反应的破坏可能导致 VPS13C 相关 PD 的发病机制。
