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.
| Original language | English (US) |
|---|---|
| Article number | e202304042 |
| Journal | Journal of Cell Biology |
| Volume | 223 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2024 |
Funding
All imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the following grants from the National Institutes of Health (NIH): NIH National Investigation Agency F30 AG066333 (to W. Peng); NIH National Institute of Neurological Disorders and Stroke (NINDS) K99 NS109252 and R00 NS109252 (to Y.C. Wong); and NIH NINDS R35 NS122257 (to D. Kranic); and from the Deutsche Forschungsgemeinschaft SCHW 866/6-1 and SCHW 866/7-1 (to M. Schwake).
Keywords
- Neuroscience
- Organelles
- Stem cells
ASJC Scopus subject areas
- Cell Biology
