Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration.
1. Nat Commun. 2020 Mar 13;11(1):1386. doi: 10.1038/s41467-020-15119-w. Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration. Choi I(1), Zhang Y(1), Seegobin SP(1), Pruvost M(1), Wang Q(1)(2), Purtell K(1), Zhang B(2), Yue Z(3). Author information: (1)Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (2)Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. (3)Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. zhenyu.yue@mssm.edu. 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 α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-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-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy. DOI: 10.1038/s41467-020-15119-w PMCID: PMC7069981 PMID: 32170061
