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Published on: April 13, 2017
Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration
Insup Choi1, Yuanxi Zhang1, Steven P Seegobin1
1Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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.
Insights
Microglia protect the brain by clearing toxic alpha-synuclein via a process called synucleinphagy. Disrupting this pathway leads to neurodegeneration, highlighting microglia
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglia are crucial for maintaining brain homeostasis by clearing cellular debris.
- The role of microglia in neurodegenerative diseases, particularly in clearing alpha-synuclein, is not fully understood.
- Accumulation of misfolded alpha-synuclein is a hallmark of several neurodegenerative disorders.
Purpose of the Study:
- To investigate the neuroprotective role of microglia in clearing neuron-released alpha-synuclein.
- To elucidate the molecular mechanisms underlying microglial alpha-synuclein clearance, specifically selective autophagy (synucleinphagy).
Main Methods:
- Activation of microglia by neuronal alpha-synuclein.
- Engulfment of alpha-synuclein into autophagosomes for degradation via selective autophagy (synucleinphagy).
- Investigated the role of Toll-like receptor 4 (TLR4), NF-κB signaling, and p62/SQSTM1 in synucleinphagy.
- Utilized mouse models expressing human alpha-synuclein to study the impact of disrupted microglial autophagy on dopaminergic neuron degeneration.
Main Results:
- Neuronal alpha-synuclein activates microglia to initiate synucleinphagy, a selective autophagy pathway for alpha-synuclein degradation.
- Microglial synucleinphagy is dependent on Toll-like receptor 4 (TLR4), which upregulates p62/SQSTM1 via NF-κB signaling.
- p62/SQSTM1 is essential for the formation of ubiquitinated alpha-synuclein aggregates targeted for autophagic degradation.
- Disruption of microglial autophagy in mice leads to alpha-synuclein accumulation and dopaminergic neuron loss.
Conclusions:
- Microglia exert a neuroprotective effect by clearing toxic alpha-synuclein through TLR4-NF-κB-p62 mediated synucleinphagy.
- This study identifies a critical mechanism for preventing alpha-synuclein aggregation and subsequent neurodegeneration.
- Targeting microglial synucleinphagy represents a potential therapeutic strategy for alpha-synucleinopathies.
