Microglia clear neuron-released ?-synuclein via selective autophagy and prevent neurodegeneration.
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ABSTRACT: 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 ?-synuclein. Neuronal ?-synuclein activates microglia, which in turn engulf ?-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-?B signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of ?-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human ?-synuclein promotes the accumulation of misfolded ?-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of ?-synuclein via TLR4-NF-?B-p62 mediated synucleinphagy.
SUBMITTER: Choi I
PROVIDER: S-EPMC7069981 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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