Microglia clear neuron-released a-synuclein via selective autophagy and prevent neurodegeneration
Microglia clear neuron-released a-synuclein via selective autophagy and prevent neurodegeneration
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DOI：
10.1038/s41467-020-15119-w
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发表时间：
2020-03-13
影响因子：
16.6
通讯作者：
Yue, Zhenyu
中科院分区：
文献类型：
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作者：
Choi, Insup;Zhang, Yuanxi;Yue, Zhenyu
小胶质细胞通过去除髓鞘和细胞碎片等神经元衍生成分来维持大脑的动态平衡。将小胶质细胞与神经退行性疾病联系起来的证据正在增加；然而，确切的机制仍然知之甚少。在此，我们报告了小胶质细胞在清除神经元释放的α-突触核蛋白中的神经保护作用。神经元α-突触核蛋白激活小胶质细胞，进而将a-突触核蛋白吞噬到自噬小体中，通过选择性自噬(称为突触核蛋白吞噬)进行降解。突触核蛋白吞噬需要小胶质细胞Toll样受体4(TLR4)的存在，TLR4通过NF-kappa B信号通路诱导p62/SQSTM1转录上调。自噬受体p62的诱导对于α-突触核蛋白/泛素阳性斑点的形成是必要的，这些斑点被自噬降解。最后，在表达人类α-突触核蛋白的小鼠中，小胶质细胞自噬的中断促进了错误折叠的a-突触核蛋白的积累，并导致中脑多巴胺能神经元退化。因此，我们的研究确定了小胶质细胞通过TLR4-NF-kappa B-p62介导的突触核蛋白吞噬清除a-突触核蛋白的神经保护功能。
Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released a-synuclein. Neuronal a-synuclein activates microglia, which in turn engulf a-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-kappa B signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of alpha-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human a-synuclein promotes the accumulation of misfolded a-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of a-synuclein via TLR4-NF-kappa B-p62 mediated synucleinphagy.