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Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice, Autophagy, 31 Jan 2020

发布时间:2020年01月31日

Autophagy, 31 January, 2020,DOI:http://dx.doi.org/10.1080/15548627.2020.1719723

Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice

Jinbo Cheng, Yajin Liao, Yuan Dong, Han Hu, Nannan Yang, Xiangxi Kong, Shuoshuo Li, Xiaoheng Li, Jifeng Guo, Lixia QinORCID Icon, Jiezhong Yu, Cungen Ma, Jianke Li, Mingtao Li, Beisha Tang & Zengqiang Yuan

Abstract

Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)–cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD.

文章链接:https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1719723

 

 

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