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The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair

Shan Li1, Shidong Xu1, Feng Li1

  • 1Center for Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, School of Life Sciences, Yunnan University, Kunming, China.

The EMBO Journal
|May 29, 2026
PubMed

Insights

The C9orf72/SMCR8 complex is vital for microglial health, repairing damaged lysosomes to prevent neuroinflammation. Its loss causes age-dependent microglial dysfunction and disease.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Microglia are key in brain inflammation and neurodegeneration.
  • C9orf72 gene mutations are linked to ALS and FTD, affecting the autophagy-lysosomal pathway.
  • The specific function of C9orf72 in microglia was previously unknown.

Purpose of the Study:

  • To investigate the role of C9orf72 in microglial function and homeostasis.
  • To determine the molecular mechanisms by which C9orf72 regulates microglial health.
  • To explore the link between C9orf72, lysosomal repair, and neuroinflammation.

Main Methods:

  • Studied C9orf72/SMCR8 complex function in microglial homeostasis using mouse models.
  • Induced lysosomal damage in microglia with a lysosomotropic agent.
  • Analyzed lysosomal repair mechanisms, including RAB8A and ESCRT machinery recruitment.
  • Examined age-dependent neuroinflammation and microgliosis in C9orf72/SMCR8 deficient mice.

Main Results:

  • Loss of C9orf72/SMCR8 in mice leads to age-dependent neuroinflammation and microgliosis.
  • Microglia in aged C9orf72/SMCR8 deficient mice exhibit lysosomal damage and galectin-3 accumulation.
  • C9orf72/SMCR8 deficiency impairs lysosomal repair by disrupting RAB8A-ESCRT recruitment to damaged lysosomes.
  • Mutant microglia show accumulation of hyperphosphorylated, mislocalized GTP-bound RAB8A.

Conclusions:

  • The C9orf72/SMCR8 complex is essential for microglial homeostasis by promoting lysosomal membrane repair.
  • Dysfunctional lysosomal repair in microglia due to C9orf72/SMCR8 loss contributes to neuroinflammation.
  • Targeting the C9orf72/SMCR8-mediated lysosomal repair pathway may offer therapeutic strategies for neurodegenerative diseases.

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