biostudies-literatureUnknown9(16)Banerjee PAlthough microglial activation is widely found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the underlying mechanism(s) are poorly understood. Here, using human-induced pluripotent stem cell-derived microglia-like cells (hiPSC-MG) harboring the most common ALS/FTD mutation (<i>C9orf72</i>, mC9-MG), gene-corrected isogenic controls (isoC9-MG), and <i>C9orf72</i> knockout hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated immune response upon stimulation with lipopolysaccharide. Analysis of the C9ORF72 interactome revealed that C9ORF72 interacts with regulators of autophagy and functional studies showed impaired initiation of autophagy in mC9-MG and C9KO-MG. Coculture studies with motor neurons (MNScience advanceseabq0651https://www.ebi.ac.uk/biostudies/studies/S-EPMC10121169biostudies-literatureCell-autonomous immune dysfunction driven by disrupted autophagy in <i>C9orf72</i>-ALS iPSC-derived microglia contributes to neurodegeneration.PMC10121169Cooper JMehta ARJames OGNewton JSmith CAlessi DRSelvaraj BTNanda JMcDade KPaza ELongden JStory DSalzinger ANirujogi RSBurr KPal SPriller JChandran SBanerjee PfalseCell-autonomous immune dysfunction driven by disrupted autophagy in <i>C9orf72</i>-ALS iPSC-derived microglia contributes to neurodegeneration.Although microglial activation is widely found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the underlying mechanism(s) are poorly understood. Here, using human-induced pluripotent stem cell-derived microglia-like cells (hiPSC-MG) harboring the most common ALS/FTD mutation (<i>C9orf72</i>, mC9-MG), gene-corrected isogenic controls (isoC9-MG), and <i>C9orf72</i> knockout hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated immune response upon stimulation with lipopolysaccharide. Analysis of the C9ORF72 interactome revealed that C9ORF72 interacts with regulators of autophagy and functional studies showed impaired initiation of autophagy in mC9-MG and C9KO-MG. Coculture studies with motor neurons (MN2023-01-01T00:00:00Z2023 Apr2025-04-25T19:44:11.349Z2025-04-06T08:03:11.172ZS-EPMC101211693708353010.1126/sciadv.abq0651