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Coronin1A Regulates the Trafficking of Alpha Synuclein in Microglia

Karl E Biggs1,2, Emma N Fikse1, Faith L Anderson1

  • 1Departments of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03766.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|January 21, 2025
PubMed

Insights

Coronin1A (Coro1A) in microglia protects against alpha synuclein toxicity in Parkinson's disease by shunting protein aggregates away from lysosomes. Loss of Coro1A increases cell death and inflammasome activation.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Microglia, the brain's immune cells, respond to toxic protein aggregates in neurodegenerative diseases like Parkinson's.
  • Activation of the NLRP3 inflammasome in microglia leads to inflammation and cell death.
  • Alpha-synuclein (αsyn) preformed fibrils (PFFs) are key pathological protein aggregates in Parkinson's disease.

Purpose of the Study:

  • To investigate the role of Coronin1A (Coro1A) in microglial response to αsyn PFFs.
  • To identify cellular mechanisms by which microglia handle pathological protein aggregates.
  • To explore Coro1A's involvement in Parkinson's disease pathogenesis.

Main Methods:

  • Primary mouse microglia were exposed to microbial stressors and αsyn PFFs.
  • Extracellular vesicles (EVs) released by microglia were analyzed for Coro1A content.
  • αsyn trafficking, lysosomal integrity, and cell death pathways were assessed in Coro1A-deficient microglia.
  • Postmortem human brain tissue from Parkinson's disease patients was analyzed.

Main Results:

  • Microglia release Coro1A in EVs in an NLRP3-dependent manner under general activation, but surprisingly not with αsyn PFFs.
  • Loss of Coro1A in microglia leads to increased αsyn trafficking to lysosomes, causing lysosomal membrane permeabilization.
  • Coro1A deficiency results in enhanced αsyn PFF-induced cytotoxicity, elevated cytosolic cathepsin B, and a PARP cleavage product.
  • Elevated Coro1A protein levels were observed in the mesencephalon of human Parkinson's disease brains.

Conclusions:

  • Coro1A acts as a crucial regulator, shunting pathological αsyn away from lysosomes to a secretory pathway via EVs, thereby mitigating lysosomal stress.
  • Loss of Coro1A function in microglia exacerbates αsyn-induced lysosomal damage and cytotoxicity, contributing to neurodegeneration.
  • These findings highlight Coro1A's protective role in microglia against inflammasome activation and pyroptotic cell death, relevant to Parkinson's disease progression.
Keywords:
NLRP3Parkinson's diseasealpha synucleinextracellular vesiclelysosomemicroglia

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