GSE98288 Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS

Contributors : Claire Hall ; Zhi Yao ; Minee Choi ; Giulia Tyzack ; Andrea Serio ; Raphaelle Luisier ; Jasmine Harley ; Elisavet Preza ; Charlie Arber ; Sarah J Crisp ; P M Watson ; Dimitri M Kullmann ; Andrey Abramov ; Selina Wray ; Russell Burley ; Sam H Loh ; Miguel L Martins ; Molly M Stevens ; Nicholas Luscombe ; Christopher Sibley ; Andras Lakatos ; Jernej Ule ; Sonia Gandhi ; Rickie PataniSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensMotor 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. Herewe optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (>85%) functional populations of spinal cord MNs and ACs. We identifysignificantlyincreased 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 additionallyidentify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research