p38-TFEB Pathways Promote Microglia Activation Through Inhibiting CMA-mediated NLRP3 Degradation in Parkinson's Disease

Abstract BackgroundParkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by chronic neuroinflammation, autophagy dysfunction and α-synuclein accumulation in the form of Lewy bodies. Previous studies showed that misfolded α-synuclein upregulates the inflammatory and autophagy dysfunction in microglial cell. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the inter-relationship between autophagy deficiency and neuroinflammation induced by α-synuclein accumulation is not well understood.MethodsWe investigated the impact of p38-TFEB-NLRP3 pathways on neuroinflammation in the α-synucleinA53T PD models, using a combination of immunoblotting, immunofluorescence, immunocytochemistry, flow cytometry, ELISA, and a series of behavioral texts.ResultsIn the present study, we showed NLRP3 was degraded through chaperone-mediated autophagy (CMA) in microglia cell. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Overexpress mice and BV2 cells with α-synuclein A53T mutant active P38, which inhibit the master transcriptional activator of autophagy, TEEB in BV2 cells. Notably, inhibition p38 had a protective effect on Parkinson's disease model, which depend on suppressing the activation of NLRP3 inflmmasome pathway. Importantly, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevent neurodegeneration in vitro, but also alleviates movement impairment in α-synucleinA53T-tg mice model of Parkinson’s disease. ConclusionOur research reveals an endogenous regulatory mechanism of NLRP3 turnover and microglia-dopaminergic neuron interaction, which may be a potential therapeutic strategy for Parkinson’s disease.