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