biostudies-literatureHall CECancer Research UKEuropean Research CouncilAction Medical ResearchThe Francis Crick InstituteMedical Research CouncilNational Institute for Health Research (NIHR)Wellcome TrustAcademy of Medical Sciences1739-1749https://www.ebi.ac.uk/biostudies/studies/S-EPMC5464993biostudies-literatureUnknown19(9)Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attCell reportsProgressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.PMC5464993MR/L012677/1G116/147101149/Z/13/ZNIHR-INF-0413616417104033/Z/14/ZMC_U13267451810110MR/L01095X/116358MR/P008658/1MR/M02492X/1101149/Z/13/A100172/Z/12/Z103760/Z/14/ZAMS-SGCL5-Gandhi1725Hall CEBurley RMartins LMLoh SHYLuisier RCrisp SJHarley JLuscombe NMPreza EStevens MMChoi MTyzack GEWatson PMDWray SSerio AYao ZGandhi SArber CLakatos AKullmann DMUle JAbramov AYSibley CRPatani RfalseProgressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not att2017-01-01T00:00:00Z2017 May2026-05-05T08:23:59.79Z2025-05-29T20:49:19.39ZS-EPMC54649932856459410.1016/j.celrep.2017.05.024