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Differential microglial responses to structurally distinct alpha-synuclein polymorphs.

Katherine Chang1, Jina Kim2,3, Michiyo Iba1

  • 1Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.

Molecular Brain
|December 6, 2025
PubMed
Summary
This summary is machine-generated.

Distinct alpha-synuclein aggregates in synucleinopathies trigger varying microglial neuroinflammation. Kinetically stable oligomers and mature fibrils strongly activate microglial responses, highlighting structure-dependent inflammatory properties.

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Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by alpha-synuclein aggregation and neuroinflammation.
  • Structurally distinct alpha-synuclein aggregates exist, but their specific impact on neuroinflammation is not well understood.

Purpose of the Study:

  • To investigate the differential effects of various alpha-synuclein polymorphs on microglial neuroinflammation.
  • To determine how distinct alpha-synuclein structures influence microglial activation and Toll-like receptor (TLR) signaling.

Main Methods:

  • Human induced pluripotent stem cell-derived microglia (iMG) were exposed to different alpha-synuclein polymorphs (oligomers and fibrils).
  • Transcriptome analysis was performed to assess microglial gene expression.
  • HEK-Blue TLR reporter assays were used to measure Toll-like receptor agonist activities.

Main Results:

  • Kinetically stable alpha-synuclein oligomers and mature fibrils induced microglial cytokine and chemokine expression.
  • All tested alpha-synuclein polymorphs commonly activated the Toll-like receptor signaling cascade.
  • Kinetically stable alpha-synuclein oligomers specifically activated TLR2 and TLR4, while sonicated fibrils activated TLR4.

Conclusions:

  • Structurally distinct alpha-synuclein polymorphs possess unique neuroinflammatory properties.
  • The specific structure of alpha-synuclein aggregates influences the degree and type of microglial inflammatory response.
  • These findings contribute to understanding the complex interplay between alpha-synuclein pathology and neuroinflammation in synucleinopathies.