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Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity.
Ferlazzo, Giorgia Maria; Gambetta, Anna Maria; Amato, Sonia; Cannizzaro, Noemi; Angiolillo, Silvia; Arboit, Mattia; Diamante, Linda; Carbognin, Elena; Romani, Patrizia; La Torre, Federico; Galimberti, Elena; Pflug, Florian; Luoni, Mirko; Giannelli, Serena; Pepe, Giuseppe; Capocci, Luca; Di Pardo, Alba; Vanzani, Paola; Zennaro, Lucio; Broccoli, Vania; Leeb, Martin; Moro, Enrico; Maglione, Vittorio; Martello, Graziano.
Afiliación
  • Ferlazzo GM; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Gambetta AM; Aptuit (Verona) S.r.l., an Evotec Company, Campus Levi-Montalcini, 37135, Verona, Italy.
  • Amato S; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Cannizzaro N; Department of Biology, University of Padova, Via U. Bassi 58B, 35131, Padua, Italy.
  • Angiolillo S; Department of Biology, University of Padova, Via U. Bassi 58B, 35131, Padua, Italy.
  • Arboit M; Department of Neuroscience, University of Padova, Via Belzoni, 160, 35131, Padua, Italy.
  • Diamante L; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Carbognin E; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Romani P; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • La Torre F; Department of Biology, University of Padova, Via U. Bassi 58B, 35131, Padua, Italy.
  • Galimberti E; Department of Biology, University of Padova, Via U. Bassi 58B, 35131, Padua, Italy.
  • Pflug F; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Luoni M; Department of Biology, University of Padova, Via U. Bassi 58B, 35131, Padua, Italy.
  • Giannelli S; Max Perutz Laboratories Vienna, University of Vienna, Vienna Biocenter, Dr Bohr Gasse 9, 1030, Vienna, Austria.
  • Pepe G; Max Perutz Laboratories Vienna, University of Vienna, Vienna Biocenter, Dr Bohr Gasse 9, 1030, Vienna, Austria.
  • Capocci L; Division of Neuroscience, San Raffaele Scientific Institute, 20132, Milan, Italy.
  • Di Pardo A; Division of Neuroscience, San Raffaele Scientific Institute, 20132, Milan, Italy.
  • Vanzani P; IRCCS Neuromed, 86077, Pozzilli, Italy.
  • Zennaro L; IRCCS Neuromed, 86077, Pozzilli, Italy.
  • Broccoli V; IRCCS Neuromed, 86077, Pozzilli, Italy.
  • Leeb M; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Moro E; Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
  • Maglione V; Division of Neuroscience, San Raffaele Scientific Institute, 20132, Milan, Italy.
  • Martello G; CNR Institute of Neuroscience, 20854, Vedrano al Lambro, Italy.
Nat Commun ; 14(1): 3962, 2023 07 05.
Article en En | MEDLINE | ID: mdl-37407555
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Huntington / Enfermedades Neurodegenerativas Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Huntington / Enfermedades Neurodegenerativas Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido