title: Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming.
abstract: Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany. Electronic address: sergio.gascon@med.uni-muenchen.de.
authors.forename: Sergio
authors.initials: S
authors.lastname: Gascón
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Murenu
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Masserdotti
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Complutense University, Avenue Puerta de Hierro, 28040 Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Gianluca L
authors.initials: GL
authors.lastname: Russo
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Petrik
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
authors.forename: Aditi
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
authors.forename: Christophe
authors.initials: C
authors.lastname: Heinrich
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
authors.forename: Marisa
authors.initials: M
authors.lastname: Karow
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, 9016 Dunedin, New Zealand.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Center Munich, Neuherberg, 85764 Neuherberg, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Center Munich GmbH, 85764 Neuherberg, Germany; Center of Life and Food Sciences Weihenstephan, Technical University Munich, 85354 Freising, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Institute of Experimental Genetics, Helmholtz Center Munich GmbH, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Merowingerplatz 1a, 40225 Düsseldorf, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berndt
authors.affiliation: Institute of Developmental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: José P Friedmann
authors.initials: JP
authors.lastname: Angeli
authors.affiliation: Institute of Developmental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Berninger
authors.affiliation: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany; Excellence Cluster of Systems Neurology (SYNERGY), 80336 Munich, Germany. Electronic address: magdalena.goetz@helmholtz-muenchen.de.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Götz
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D000067470:Cellular Reprogramming Techniques; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse