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

• Published in: Development (Cambridge) Vol. 149; no. 20
• Main Authors: Romero-Morales, Alejandra I, Robertson, Gabriella L, Rastogi, Anuj, Rasmussen, Megan L, Temuri, Hoor, McElroy, Gregory Scott, Chakrabarty, Ram Prosad, Hsu, Lawrence, Almonacid, Paula M, Millis, Bryan A, Chandel, Navdeep S, Cartailler, Jean-Philippe, Gama, Vivian
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.10.2022
• Subjects: Human Development; Humans; Induced Pluripotent Stem Cells - metabolism; Leigh Disease - genetics; Leigh Disease - metabolism; Mutation - genetics; Neural Development; Neural Stem Cells - metabolism; Organoids - metabolism; Stem Cells & Regeneration; Leigh syndrome; Mitochondria; Oxidative phosphorylation; Brain organoids; Neural precursor cells; Stem cells; Glycolysis; Neural rosettes
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.199914

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 human induced pluripotent stem cells (iPSCs) from three LS patient-derived fibroblast lines. Using whole-exome and mitochondrial sequencing, we identified unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). These LS patient-derived iPSC lines were viable and capable of differentiating into progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS patient-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 precursor 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 to study Leigh syndrome.