Microglia Clear Neuron-released α-Synuclein via Selective Autophagy and Prevent Neurodegeneration

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 is initiated by the interaction of α-synuclein with Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway without causing TLR4 endocytosis. 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 novel neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated Synucleinphagy.