期刊
JOURNAL OF CELL BIOLOGY
卷 221, 期 7, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202106046
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资金
- National Institute of Health (NIH) [NS36251, DA018343]
- Chan Zuckerberg initiative DAF [2020-221912]
- Parkinson Foundation [PF-RCE-1946]
- NIH [F31NS110229-01, GM105718, R01 AR069876]
- AHA-Allen Initiative in Brain Health and Cognitive Impairment award [19PABH134610000]
- NIH Medical Scientist Training Program Training Grant [T32GM007205]
- Michael J. Fox Foundation for Parkinson's Research
- Aligning Science Across Parkinson's initiative
- Michael J. Fox Foundation for Parkinson [ASAP000580]
Mutations in the VPS13C gene cause early-onset autosomal recessive Parkinson's disease. This gene encodes a lipid transfer protein localized to contact sites between the endoplasmic reticulum and late endosomes/lysosomes. Depleting VPS13C results in altered lipid profiles in lysosomes and activates pathways associated with Parkinson's disease.
Mutations in VPS13C cause early-onset, autosomal recessive Parkinson's disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.
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