Journal Article

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

Pruvost, Mathilde, Seegobin, Steven P., Zhang, Yuanxi, Wang, Qian, Zhang, Bin, Choi, Insup, Yue, Zhenyu, Purtell, Kerry

2020

Overview

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. Microglia perform important supporting roles for neurons in the brain. Here, the authors show that microglia clear neuron-derived α-synuclein through selective autophagy (synucleinphagy) to prevent accumulation of misfolded α-synuclein and subsequent neurodegeneration in a mouse model of disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 14 / 14/63 / 631/378/2596/1953 / 631/80/39/2346 / 64/60 / alpha-Synuclein - metabolism / Animals / Autoantigens - metabolism / Autophagy / Autophagy - physiology / Bioaccumulation / Brain / Brain - metabolism / Degeneration / Disease Models, Animal / Disruption / Dopamine receptors / Dopaminergic Neurons - metabolism / Female / HEK293 Cells / Homeostasis / Humanities and Social Sciences / Humans / Mesencephalon / Mesencephalon - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Microglia / Microglia - metabolism / Microglia - pathology / multidisciplinary / Myelin / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - metabolism / Neuroprotection / NF-kappa B - metabolism / NF-κB protein / Phagocytosis / Phagosomes / Science / Science (multidisciplinary) / Signal Transduction / Synuclein / TLR4 protein / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Transcription / Ubiquitin