Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.

Autor:	Sonsalla G; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany; Graduate School of Systemic Neurosciences, BMC, LMU Munich, Planegg-Martinsried 82152 Germany., Malpartida AB; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany; International Max Planck Research School (IMPRS) for Molecular Life Sciences, Planegg-Martinsried 82152, Germany., Riedemann T; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany., Gusic M; Institute of Neurogenomics, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany., Rusha E; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany., Bulli G; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany; Graduate School of Systemic Neurosciences, BMC, LMU Munich, Planegg-Martinsried 82152 Germany., Najas S; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany., Janjic A; Anthropology and Human Genomics, Faculty of Biology, LMU Munich, Planegg-Martinsried 82152, Germany., Hersbach BA; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany; Graduate School of Systemic Neurosciences, BMC, LMU Munich, Planegg-Martinsried 82152 Germany., Smialowski P; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany; Biomedical Center Munich, Bioinformatic Core Facility, LMU Munich, Planegg-Martinsried 82152, Germany., Drukker M; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Gorlaeus Building, 2333 CC RA, Leiden, the Netherlands., Enard W; Anthropology and Human Genomics, Faculty of Biology, LMU Munich, Planegg-Martinsried 82152, Germany., Prehn JHM; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland., Prokisch H; Institute of Neurogenomics, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany; Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Götz M; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany; Excellence Cluster of Systems Neurology (SYNERGY), Munich, Germany. Electronic address: magdalena.goetz@bmc.med.lmu.de., Masserdotti G; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg 85764, Germany; Biomedical Center Munich, Physiological Genomics, LMU Munich, Planegg-Martinsried 82152, Germany. Electronic address: giacomo.masserdotti@helmholtz-munich.de.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Apr 03; Vol. 112 (7), pp. 1117-1132.e9. Date of Electronic Publication: 2024 Jan 23.
DOI:	10.1016/j.neuron.2023.12.020
Abstrakt:	Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming. Competing Interests: Declaration of interests M. Götz is member of the advisory board of Neuron. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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