Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Romero-Morales, A. I.; Rastogi, A.; Temuri, H.; Rasmussen, M. L.; McElroy, G. S.; Hsu, L.; Almonacid, P. M.; Millis, B. A.; Chandel, N. S.; Cartailler, J.-P.; Gama, V.

doi:10.1101/2020.04.21.054361

bioRxiv · 10.1101/2020.04.21.054361

Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Romero-Morales, A. I.·Rastogi, A.·Temuri, H.·Rasmussen, M. L.·McElroy, G. S.·Hsu, L.·Almonacid, P. M.·Millis, B. A.·Chandel, N. S.·Cartailler, J.-P.·Gama, V.

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Abstract

Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions, caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated iPSCs from three patient-derived LS fibroblast lines and identified, by whole-exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS-derived iPSC lines were viable and generally capable of differentiating into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS-derived cerebral organoids showed defects in neural epithelial bud generation, size, and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural progenitor cells with abnormal mitochondrial morphology characterized by fragmentation and disorganization and showed an increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that can be used as LS model systems.

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Romero-Morales, A. I., Rastogi, A., Temuri, H., Rasmussen, M. L., McElroy, G. S., Hsu, L., Almonacid, P. M., Millis, B. A., Chandel, N. S., Cartailler, J.-P., Gama, V.. 2020-04-22. Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis. https://doi.org/10.1101/2020.04.21.054361

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