Human iPSC-derived cerebral organoids model features of Leigh syndrome and reveal abnormal corticogenesis.
Development
; 149(20)2022 10 15.
Article
en En
| MEDLINE
| ID: mdl-35792828
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 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 100â
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de Leigh
/
Células Madre Pluripotentes Inducidas
/
Células-Madre Neurales
Límite:
Humans
Idioma:
En
Revista:
Development
Asunto de la revista:
BIOLOGIA
/
EMBRIOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos