TRPV2 protects dopaminergic neurons via ferroptosis inhibition in Parkinson's disease

Ferroptosis, the cell death induced by iron accumulation, contributes to the pathogenesis of Parkinson's disease (PD). While transient receptor potential vanilloid 2 (TRPV2) is known to mediate pathological processes in neurodegenerative diseases, its specific role in ferroptosis in PD remains largely unknown. This study aims to investigate the underlying mechanisms of TRPV2 in PD.

An MPTP-induced mouse model of PD and MPP⁺-induced SH-SY5Y cellular model were established. To investigate the role and mechanism of TRPV2 in PD, AAV2/9 TRPV2 was injected into the substantia nigra (SN) of mice. In parallel, SH-SY5Y cells were transfected with si-TRPV2, pc-TRPV2, TRPV2-S339A, or pc-PTEN-induced putative kinase 1 (PINK1) plasmids, or treated with ferroptosis inhibitor ferrostatin-1.

Our results demonstrated that TRPV2 expression was dramatically decreased in PD, particularly in dopaminergic neurons. Notably, overexpression of TRPV2 obviously improved neurological impairment and ferroptosis, whereas TRPV2 knockdown strongly exacerbated these effects. Interestingly, ferrostatin-1 reversed the detrimental effect of TRPV2 knockdown in PD in vitro. Furthermore, bioinformatics analysis and our experimental results indicate that TRPV2 is phosphorylated by PINK1 at serine 339. Additionally, the protective roles of PINK1 overexpression in inhibiting ferroptosis were abolished by TRPV2 interference or TRPV2-S339A.

These findings implicate a neuroprotective role for TRPV2 in PD, potentially through a mechanism involving its regulation of ferroptosis via phosphorylation by PINK1.