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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]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126359 | 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 [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.

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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

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

Leigh Syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing.

Project description:Leigh Syndrome (LS) is the most common early-onset, progressive mitochondrial encephalopathy usually leading to early death. The single most prevalent cause of LS is occurrence of mutations in the hSurf1 gene. LSSurf1 patients show a marked and specific decrease in the activity of mitochondrial respiratory chain complex IV (cytochrome c oxidase, COX). hSurf1 encodes an inner membrane mitochondrial protein involved in COX assembly. We established a D. melanogaster model of LS based on the post-transcriptional silencing of CG9943, the Drosophila homolog of hSurf1. Knock down of Surf1 was induced (i) ubiquitously, which led to larval lethality; (ii) in the mesodermal derivatives, which led to pupal lethality; (iii) in the central nervous system, which allowed survival; and (iv) at specific developmental stages. A biochemical characterization was carried out in knock down individuals, which unexpectedly revealed defects in all complexes of the mitochondrial respiratory chain (MRC) included the F-ATP synthase (complex V) in larvae, and a COX-specific impairment in adults. Silencing of Surf1 expression in Drosophila S2R+ cells led to loss of COX activity associated with decreased oxygen consumption. We conclude that Surf1 is essential for COX activity and mitochondrial function in D. melanogaster, and provide a new tool to clarify the pathogenic mechanisms of LS.

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Project description:Our understanding of the mechanisms underlying the human neuronal pathology associated with impaired oxidative phosphorylation (OXPHOS) is hampered by a lack of effective model systems. Using patient-derived induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 engineering, we developed a human model of Leigh syndrome (LS) caused by mutations in the gene SURF1, which is the most frequent and severe manifestation of mitochondrial disease in children. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal differentiation and morphogenesis of two-dimensional (2D) neuronal cultures and of three-dimensional (3D) cerebral organoids. The phenotypes emerged at the level of neural progenitor cells (NPCs). Mutant NPCs could not shift to OXPHOS and retained a glycolytic proliferative state that failed to support neuronal morphogenesis. Improving NPC bioenergetics by increasing mitochondrial biogenesis via bezafibrate treatment restored early morphogenesis. SURF1 gene augmentation also counteracted the phenotypes, while exposure to hypoxia did not lead to amelioration. Our findings provide mechanistic insights and suggest therapeutic avenues for mitochondrial disease, a rare disease with major unmet medical need.

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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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Ablation of mitochondrial rhomboid Parl causes Leigh syndrome

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2018-11-21 | PXD008908 | Pride

E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE TRANSLATION FIDELITY DURING BRAIN DEVELOPMENT

Project description:Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

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

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