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Synucleinphagy: a microglial "community cleanup program" for neuroprotection.

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  • 1Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York, NY, USA.

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Microglia clear toxic alpha-synuclein (SNCA) via selective autophagy, termed "synucleinphagy," protecting against Parkinson disease hallmarks. Impaired microglial autophagy leads to neurodegeneration.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Alpha-synuclein (SNCA) aggregation in Lewy bodies characterizes Parkinson disease (PD) and dementia with Lewy body (DLB).
  • Extracellular SNCA can spread between cells, contributing to synucleinopathy progression.
  • Microglia, the brain's immune cells, play a role in clearing cellular debris and pathogens.

Purpose of the Study:

  • To investigate the mechanism by which microglia engulf and degrade extracellular SNCA.
  • To elucidate the role of microglial autophagy in maintaining SNCA homeostasis.
  • To determine the neuroprotective function of microglia in synucleinopathies.

Main Methods:

  • Utilized microglia-specific autophagy-deficient mice for in vivo and in vitro studies.
  • Investigated the involvement of SQSTM1/p62-mediated selective autophagy.
  • Examined the role of toll-like receptor 4 (TLR4) and NF-κB signaling pathway.

Main Results:

  • Microglia engulf and degrade neuron-released SNCA via SQSTM1/p62-mediated selective autophagy, termed 'synucleinphagy'.
  • This process is dependent on TLR4, which upregulates SQSTM1/p62 transcription through the NF-κB pathway.
  • Disruption of microglial autophagy leads to SNCA accumulation and dopaminergic neuron loss.

Conclusions:

  • Microglia exert a neuroprotective effect in synucleinopathies through an autophagy-dependent 'community cleanup program'.
  • Targeting microglial autophagy may offer a therapeutic strategy for Parkinson disease and related disorders.