C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.

ABSTRACT: The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by t

SUBMITTER: Mearelli M 

PROVIDER: S-EPMC12667002 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature