TY - JOUR T1 - Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis JF - bioRxiv DO - 10.1101/2020.04.21.054361 SP - 2020.04.21.054361 AU - Alejandra I. Romero-Morales AU - Anuj Rastogi AU - Hoor Temuri AU - Megan L. Rasmussen AU - Gregory Scott McElroy AU - Lawrence Hsu AU - Paula M. Almonacid AU - Bryan A. Millis AU - Navdeep S. Chandel AU - Jean-Philippe Cartailler AU - Vivian Gama Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/22/2020.04.21.054361.abstract N2 - Leigh syndrome (LS) is a rare, inherited neuro-metabolic disorder that presents with bilateral brain lesions. This disease is caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated induced pluripotent stem cells (iPSCs) from three widely available LS fibroblast lines and identified, through whole exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS derived cell lines were viable and able to differentiate into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. The DLD-mutant line showed decreased neural rosette (NR) formation, and there were differences in NR lumen area in all three LS lines compared to control. LS-derived cerebral organoids showed defects in neural epithelial bud generation and reduced size when grown for 100 days. Loss of cortical architecture and markers were detected at days 30 and 100. The MT-ATP6/PDH line produced organoid neural progenitor cells with an abnormal mitochondrial morphology characterized by fragmentation and disorganization, and demonstrated increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that could be used as LS model systems.Competing Interest StatementThe authors have declared no competing interest. ER -