MAPK14-TFEB yolları, Parkinson hastalığında CMA aracılı NLRP3 bozulmasını inhibe ederek mikroglia aktivasyonunu teşvik eder

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Abstract Background Parkinson’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 SNCA(α-synuclein) accumulation in the form of Lewy bodies. Previous studies show that misfolded SNCA upregulate the inflammatory cascade through NOX activation, which elevated ROS production in microglial cell. However, it’s still not elucidated about the molecular mechanisms between autophagy deficiency and neuroinflammation induced by SNCA accumulation in microglia.Methods We overexpress mice and BV2 cells with SNCAA53T mutant as models of early-onset Parkinson's disease and identified the mechanisms that MAPK14-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease by a series of methods of molecular biology. The results of pathology and animal behavior showed that the inhibition of MAPK14 and NLRP3 had protective effect on Parkinson's disease model.Results Here, we report that MAPK14 (p38α) activates NLRP3 inflammasome via inhibiting TFEB in BV2 cells. Transcription Factor EB (TFEB) signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy(CMA). Importantly, both MAPK14 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevents neurodegeneration in vitro, but also alleviates movement impairment and SNCA/α-synuclein abnormal accumulation in SNCAA53T-tg mice model of Parkinson’s disease.Conclusion Our 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.

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