Inhibiting TRPV4 improves α-synuclein degradation through autophagy-lysosomal pathway in the MPP(+)-induced cell model of parkinson's disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder often accompanied by dementia in its advanced stages. The pathogenesis of PD dementia involves abnormal autophagy and the accumulation of phosphorylated at serine 129 α-synuclein (pS129 α-syn). Proper functioning of the autophagy-lysosomal pathway (ALP) is essential for the effective degradation of pS129 α-syn. Our previous studies implicated the calcium channel transient receptor potential vanilloid 4 (TRPV4) in dopaminergic neuron degeneration by demonstrating that its overexpression induces endoplasmic reticulum stress and inflammation, driving neuronal loss-a hallmark of PD. This study aimed to investigate the role of TRPV4 in ALP-mediated pS129 α-syn clearance in the 1-methyl-4-phenylpyridinium ion (MPP(+))-induced PC12 cells. We observed that MPP(+) upregulated TRPV4 expression, reduced cell viability, and increased pS129 α-syn levels. Critically, all these effects were reversed by TRPV4 siRNA. Furthermore, TRPV4 siRNA restored cellular autophagic flux, which was impaired by MPP(+). Treatment with either TRPV4 siRNA or TRPV4 special inhibitor HC067047 attenuated the MPP(+)-induced elevation of microtubule associated protein 1 light chain 3B (LC3B) and p62, while restoring the expression of lysosome-associated membrane protein 1 (LAMP1) and mature cathepsin D - key indicators of ALP functionality. These results suggest that TRPV4 silencing enhances α-syn degradation via the ALP, highlighting its potential as a therapeutic target for PD.