Modeling Leigh Syndrome Using Patient-Derived Neural Cells

Background: Leigh syndrome (LS) is a rare untreatable neurologicaldisorder causing psychomotor regression and developmentalabnormalities. LS is caused by mutations of nuclearDNA (nDNA) or mitochondrial DNA (mtDNA) in more than۷۵ genes of the respiratory chain. LS research presently lacksgood model systems for mechanistic studies, which hampersthe discovery of therapies. We aimed to generate human inducedpluripotent stem cells (iPSCs) from LS patients to dissectthe disease mechanisms of LSMaterials and Methods: We generated iPSCs from LS patientscarrying mutations in nDNA (in complex I and complexIV) and mtDNA (in complex V). We derived neural progenitorcells (NPCs) and neurons from patient iPSCs and analyzed theirfunctional and bioenergetics properties.Results: Neural progenitor cells (NPCs) and neurons from LSpatients show bioenergetics impairment and functional defectsincluding calcium dyshomeostasis and defective electrophysiologicalactivity. The dysfunctions became stronger the longerthe differentiation.Conclusion: Our results suggest that LS mutations impair thebioenergetics of neural progenitors and post-mitotic neurons.Our findings represent the first model system of LS and provideinsights into the mechanisms responsible for the developmentalabnormalities and neurodegeneration observed in LS patients.