VPS13C Regulates Phospho-Rab10-mediated Lysosomal Function in Human Dopaminergic Neurons

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2024 Feb 15

PMID 38358348

Authors

Leonie F Schrder

Wesley Peng

Ge Gao

Yvette C Wong

Michael Schwake

Dimitri Krainc

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.

Gao G, Shi Y, Deng H, Krainc D Nat Commun. 2025; 16(1):1982.

PMID: 40011434 PMC: 11865444. DOI: 10.1038/s41467-025-57142-9.

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