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

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Item Type:Article
Title:Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome
Creators Name:Inak, G. and Rybak-Wolf, A. and Lisowski, P. and Pentimalli, T.M. and Jüttner, R. and Glažar, P. and Uppal, K. and Bottani, E. and Brunetti, D. and Secker, C. and Zink, A. and Meierhofer, D. and Henke, M.T. and Dey, M. and Ciptasari, U. and Mlody, B. and Hahn, T. and Berruezo-Llacuna, M. and Karaiskos, N. and Di Virgilio, M. and Mayr, J.A. and Wortmann, S.B. and Priller, J. and Gotthardt, M. and Jones, D.P. and Mayatepek, E. and Stenzel, W. and Diecke, S. and Kühn, R. and Wanker, E.E. and Rajewsky, N. and Schuelke, M. and Prigione, A.
Abstract: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.
Keywords:Cultured Cells, Induced Pluripotent Stem Cells, Leigh Disease, Membrane Proteins, Metabolomics, Mitochondria, Mitochondrial Proteins, Morphogenesis, Mutation, Neurons, Organoids, Proteomics, Single-Cell Analysis, Whole Exome Sequencing
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:12
Number:1
Page Range:1929
Date:26 March 2021
Official Publication:https://doi.org/10.1038/s41467-021-22117-z
PubMed:View item in PubMed

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