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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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A unique microglia subset associated with aggressive α-synucleinopathy uncovered in a rapidly progressive multiple

Dai Matsuse1, Hiroo Yamaguchi2, Masaya Harada1

  • 1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Neurobiology of Disease
|December 1, 2025
PubMed

Insights

A new mouse model of Multiple System Atrophy-Cerebellar (MSA-C) reveals pro-inflammatory microglia driving disease progression. Targeting these specific microglia offers a potential therapeutic strategy for MSA-C and related synucleinopathies.

Area of Science:

  • Neuroscience
  • Neuroimmunology
  • Pathology

Background:

  • Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by alpha-synuclein aggregates.
  • The cerebellar variant (MSA-C) involves demyelination and glial activation in specific brain regions.
  • Existing models do not fully recapitulate MSA-C pathology and neuroinflammation.

Purpose of the Study:

  • To develop and characterize a novel mouse model for MSA-C.
  • To investigate the role of microglia in MSA-C pathogenesis.
  • To identify potential therapeutic targets for MSA-C.

Main Methods:

  • Development of a Tet-Off inducible mouse model overexpressing human A53T alpha-synuclein in oligodendrocytes.
  • Phenotypic analysis including behavioral testing, histology, and immunohistochemistry.
  • Single-cell RNA sequencing of immune cells to identify microglial subtypes.
  • Pharmacological inhibition of CSF1R to assess microglial role.

Main Results:

  • The developed mouse model recapitulated key features of MSA-C, including ataxia, demyelination, and alpha-synuclein pathology.
  • Single-cell sequencing identified a pro-inflammatory microglial subset (TLR2+, TGM2+) associated with alpha-synuclein aggregates and demyelination.
  • Inhibition of CSF1R exacerbated disease, suggesting a detrimental role for this microglial population.
  • Similar microglial populations were found in human MSA-C autopsy cases.

Conclusions:

  • The novel MSA-C mouse model effectively mimics human disease pathology and neuroinflammation.
  • A specific subset of pro-inflammatory microglia plays a critical role in MSA-C progression.
  • Targeting these microglia represents a promising therapeutic avenue for MSA-C and related synucleinopathies.
Keywords:
DemyelinationMicrogliaMultiple system atrophySingle-cell RNA sequencingTet-off systemTransgenic mouse modelΑ-Synuclein

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