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

ABSTRACT: Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but its role in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 upregulation and its accumulation on lysosomes. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find tha

SUBMITTER: Shan Li 

PROVIDER: S-SCDT-10_1038-S44318-026-00817-W | biostudies-other |

REPOSITORIES: biostudies-other