Journal Article

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

Gotthardt, Michael, Jüttner, René, Secker, Christopher, Inak, Gizem, Di Virgilio, Michela, Pentimalli, Tancredi M., Mayr, Johannes A., Diecke, Sebastian, Zink, Annika, Prigione, Alessandro, Karaiskos, Nikos, Priller, Josef, Rybak-Wolf, Agnieszka, Bottani, Emanuela, Glažar, Petar, Wanker, Erich E., Ciptasari, Ummi, Kühn, Ralf, Brunetti, Dario, Hahn, Tobias, Wortmann, Saskia B., Uppal, Karan, Meierhofer, David, Rajewsky, Nikolaus, Lisowski, Pawel, Mlody, Barbara, Jones, Dean P., Schuelke, Markus, Berruezo-Llacuna, Maria, Henke, Marie-Thérèse, Mayatepek, Ertan, Stenzel, Werner, Dey, Monishita

2021

Overview

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. Leigh syndrome (LS) is a severe neurometabolic disorder which lacks effective models. Here, the authors developed human neuronal models of LS carrying mutations in SURF1 which show impaired neuronal morphogenesis due to metabolic deficiencies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/100 / 13/51 / 14 / 14/63 / 38 / 38/91 / 42 / 42/41 / 49 / 631/532/2064/2158 / 692/617/375/366 / Bezafibrate / Cells, Cultured / Child, Preschool / CRISPR / Defects / Exome Sequencing / Gene sequencing / Glycolysis / Humanities and Social Sciences / Humans / Induced Pluripotent Stem Cells - cytology / Induced Pluripotent Stem Cells - metabolism / Leigh Disease - genetics / Leigh Disease - metabolism / Male / Membrane Proteins - genetics / Metabolic disorders / Metabolism / Metabolomics - methods / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Mitochondrial Proteins - genetics / Morphogenesis / Morphogenesis - genetics / multidisciplinary / Mutation / Neural stem cells / Neurons - cytology / Neurons - metabolism / Organoids / Organoids - metabolism / Pluripotency / Progenitor cells / Proteomics - methods / Science / Science (multidisciplinary) / Single-Cell Analysis - methods / Stem cells