Parkin regulates NLRP3 degradation through chaperone-mediated autophagy to suppress PANoptosis and protect dopaminergic neurons in Parkinson's disease.

Parkinson's Disease (PD) is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PANoptosis, a programmed inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, contributes to DA neuron degeneration in PD. The E3 ubiquitin ligase Parkin and the inflammasome sensor NOD-like receptor protein 3 (NLRP3) are known to play critical regulatory roles in DA neuron degeneration. However, whether Parkin modulated NLRP3 via chaperone-mediated autophagy (CMA) to inhibit PANoptosis remained unclear. To verify the above hypothesis, SN4741 cells and C57BL/6 mice were treated with rotenone to establish PD models. PANoptosis activation and DA neurons degeneration were observed in PD models, and these pathological manifestations were mitigated by the NLRP3 inhibitor MCC950. Besides, Parkin interacted with NLRP3, ubiquitinated its K353 residue, and then promoted NLRP3 degradation via CMA. Parkin overexpression or CMA activation alleviated DA neuron damage and PANoptosis, while K353R mutation abolished these effects. It was revealed that Parkin mediated CMA-dependent degradation of NLRP3 (targeting K353) to suppress PANoptosis and protect DA neurons in PD. CMA activators or NLRP3 inhibitors may serve as disease-modifying therapies for PD.