Abstract
BackgroundParkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood.MethodsThrough immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models.ResultsOur results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease.ConclusionOur research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD.Graphical abstractp38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.
Highlights
Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction
NLRP3 inflammasome is activated in α‐synucleinA53T‐tg mice In order to investigate the effects of α-synuclein accumulation and related toxicity, we used α-synuclein A53T transgenic mice (α-synucleinAA53T-tg mice)
We detected the dynamic changes in NLRP3 inflammasome activation through measuring the co-staining between Iba1 and NLRP3 from 3 to 9 months old in Additional file 1: Fig. S1C, which showed that the activity levels of NLRP3 in microglia increases with months
Summary
Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies have shown that neuroinflammation may be a primary cause of PD-related pathogenesis and the degeneration and loss of dopaminergic neurons Proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and IL-1β are upregulated in the cerebrospinal fluid and blood of PD patients [1]. Activated microglia release proinflammatory cytokines that lead to neuronal death, in turn, dopaminergic neurons loss exacerbates neuroinflammation. This vicious cycle is closely associated with the pathological process of PD. The mechanisms of NLRP3 inflammasome in diverse inflammatory diseases have been extensively investigated, its regulatory networks in microglia are unclear
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