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

Nat Commun. 2020 Mar 13;11(1):1386. doi: 10.1038/s41467-020-15119-w.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens / metabolism
  • Autophagy / physiology*
  • Brain / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Mesencephalon / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism*
  • Microglia / pathology
  • NF-kappa B / metabolism
  • Neurodegenerative Diseases / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism*
  • alpha-Synuclein / metabolism*


  • Autoantigens
  • NF-kappa B
  • SNCA protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • alpha-Synuclein