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Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity

Siling Du1,2, Yingyue Zhou1,3, Dian Li4

  • 1Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.

Nature Immunology
|June 26, 2025
PubMed

Insights

Microglia are vital for brain health, and their reduction in ALSP brains impairs oligodendrocyte function. Targeting CSF1R, FGFR, and STAT3 pathways may offer new treatments for ALSP and related microgliopathies.

Area of Science:

  • Neuroscience
  • Neuroimmunology
  • Genetics

Background:

  • Microglia, the brain's immune cells, require CSF1 and IL-34 signaling via CSF1R for development.
  • Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a neurodegenerative disease caused by CSF1R mutations.

Purpose of the Study:

  • To investigate the molecular mechanisms of ALSP using single-nucleus RNA sequencing.
  • To understand the role of microglia in ALSP pathogenesis and their impact on other brain cells.

Main Methods:

  • Single-nucleus RNA sequencing on postmortem brain specimens from ALSP patients and controls.
  • Analysis of gene expression and cell type-specific signatures.

Main Results:

  • ALSP brains showed a significant reduction in microglia with a distinct activation profile.
  • Decreased myelinating oligodendrocytes (OLs) and increased stress-activated neuropilin-2+ OLs were observed.
  • Astrocytes exhibited maladaptive activation and stress responses.

Conclusions:

  • Microglia are essential for oligodendrocyte myelination and regulate astrocyte repair mechanisms.
  • Therapeutic strategies targeting CSF1R, FGFR, and STAT3 pathways could benefit ALSP and other microgliopathies.

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