Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

Insup Choi, Yuanxi Zhang, Steven P. Seegobin, Mathilde Pruvost, Qian Wang, Kerry Purtell, Bin Zhang and Zhenyu Yue ()
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Insup Choi: Icahn School of Medicine at Mount Sinai
Yuanxi Zhang: Icahn School of Medicine at Mount Sinai
Steven P. Seegobin: Icahn School of Medicine at Mount Sinai
Mathilde Pruvost: Icahn School of Medicine at Mount Sinai
Qian Wang: Icahn School of Medicine at Mount Sinai
Kerry Purtell: Icahn School of Medicine at Mount Sinai
Bin Zhang: Icahn School of Medicine at Mount Sinai
Zhenyu Yue: Icahn School of Medicine at Mount Sinai

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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 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.

Date: 2020
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DOI: 10.1038/s41467-020-15119-w

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