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Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126360 | GEO | 2021/01/29

REPOSITORIES: GEO

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Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome.

Project description:Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and is currently incurable. The lack of effective models hampers our understanding of the mechanisms underlying the neuronal pathology of LS. Using patient-derived induced pluripotent stem cells and CRISPR/Cas9 engineering, we developed a human model of LS caused by mutations in the complex IV assembly gene SURF1. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal morphogenesis in mutant neural cultures and brain organoids. The defects emerged at the level of neural progenitor cells (NPCs), which retained a glycolytic proliferative state that failed to instruct neuronal morphogenesis. LS NPCs carrying mutations in the complex I gene NDUFS4 recapitulated morphogenesis defects. SURF1 gene augmentation and PGC1A induction via bezafibrate treatment supported the metabolic programming of LS NPCs, leading to restored neuronal morphogenesis. Our findings provide mechanistic insights and suggest potential interventional strategies for a rare mitochondrial disease.

| S-EPMC7997884 | biostudies-literature

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

Project description:Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and is currently incurable. The lack of effective models hampers our understanding of the mechanisms underlying the neuronal pathology of LS. Using patient-derived induced pluripotent stem cells and CRISPR/Cas9 engineering, we developed a human model of LS due to mutations in the complex IV assembly gene SURF1. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal morphogenesis in mutant neural cultures and brain organoids. The defects emerged at the level of neural progenitor cells (NPCs), which retained a glycolytic proliferative state that failed to instruct neuronal morphogenesis. LS NPCs carrying mutations in the complex I gene NDUFS4 recapitulated morphogenesis defects. Interventions supporting the metabolic programming of NPCs restored neuronal morphogenesis, including SURF1 gene augmentation and PGC1A induction via bezafibrate treatment. Our findings provide mechanistic insights and suggest interventional strategies for a rare mitochondrial disease with major unmet medical needs.

2021-01-29 | PXD019112 | Pride

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [rRNA-depleted organoids]

Project description:Mutations in the mitochondrial complex IV assembly factor SURF1 represent a major cause of Leigh syndrome (LS), a fatal neurological disorder. SURF1-deficient animals failed to recapitulate the neuronal failure of LS, which is considered an early-onset neurodegeneration. Using patient induced pluripotent stem cells (iPSCs) and genetically corrected cells, we discovered aberrant bioenergetics initiating in neural progenitor cells (NPCs) leading to impaired neuronal differentiation and maturation. iPSC-derived cerebral organoids recapitulated the neurogenesis defects and appeared smaller with reduced cortical thickness. We suggest defective neurogenesis as a central mechanism in LS pathogenesis and propose NPC function as an interventional target, which allowed us to identify SURF1 gene augmentation as a strategy for restoring neural function in this fatal disease.

2021-01-29 | GSE134453 | GEO

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [polyA RNA-seq]

2021-01-29 | GSE126358 | GEO

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [rRNA-depleted RNA-seq]

2021-01-29 | GSE126359 | GEO

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

Project description:Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

| PRJNA521698 | ENA

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [rRNA-depleted organoids]

Project description:Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [rRNA-depleted organoids]

| PRJNA555432 | ENA

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [polyA RNA-seq]

Project description:Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [polyA RNA-seq]

| PRJNA521701 | ENA

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [rRNA-depleted RNA-seq]

Project description:Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome [rRNA-depleted RNA-seq]

| PRJNA521700 | ENA

Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome.

Project description:BACKGROUND: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene. METHODS AND RESULTS: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers. CONCLUSIONS: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.

| S-EPMC2921275 | biostudies-literature

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