USP10 inhibits the degradation of α-synuclein, a pathogenic factor associated with Parkinson's disease, by inhibiting chaperone-mediated autophagy

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, particularly in the substantia nigra of the brain. α-Synuclein is a major causative factor in both familial and sporadic forms of PD, and its protein aggregates play critical roles in neuronal cell death and PD pathogenesis. This study explored the role of ubiquitin-specific protease 10 (USP10) in the regulation of α-synuclein in neuronal cells. Knockdown of USP10 in SH-SY5Y neuronal cells led to a reduction in α-synuclein levels, which was reversed by inhibiting chaperone-mediated autophagy (CMA) through lysosome-associated membrane protein 2A depletion, a protein essential for CMA. A novel CMA reporter with a specific CMA degradation motif further demonstrated that knockdown of USP10 activated CMA in neuronal cells. In addition, USP10 overexpression increased the levels of both WT and five PD-associated α-synuclein mutants, whereas a deubiquitinase-deficient USP10 mutant did not increase α-synuclein levels. This study provides new insights into the mechanisms that regulate α-synuclein proteostasis and highlights USP10 as a promising drug target for PD.