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

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

PROVIDER: PRJNA521701 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8556440.fastq.gz	Fastqsanger.gz
	SRR8556450.fastq.gz	Fastqsanger.gz
	SRR8556431.fastq.gz	Fastqsanger.gz
	SRR8556441.fastq.gz	Fastqsanger.gz
	SRR8556451.fastq.gz	Fastqsanger.gz

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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 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

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

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

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 | GSE126358 | GEO

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]

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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]

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

2021-01-29 | GSE134453 | 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: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:This SuperSeries is composed of the SubSeries listed below.

2021-01-29 | GSE126360 | GEO

The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome

Project description:The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome i.e., m.9185T>C in the mt-ATP6 gene and m.13513G>A in the mt-ND5 gene, in comparison to cybrid cells harbouring control mtDNA haplogroups or the wt m.13513G variant.

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