Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity

Giorgia Maria Ferlazzo, Anna Maria Gambetta, Sonia Amato, Noemi Cannizzaro, Silvia Angiolillo, Mattia Arboit, Linda Diamante, Elena Carbognin, Patrizia Romani, Federico La Torre, Elena Galimberti, Florian Pflug, Mirko Luoni, Serena Giannelli, Giuseppe Pepe, Luca Capocci, Alba Di Pardo, Paola Vanzani, Lucio Zennaro, Vania Broccoli, Martin Leeb, Enrico Moro, Vittorio Maglione and Graziano Martello ()
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Giorgia Maria Ferlazzo: Medical School, University of Padua
Anna Maria Gambetta: Medical School, University of Padua
Sonia Amato: University of Padova
Noemi Cannizzaro: Medical School, University of Padua
Silvia Angiolillo: Medical School, University of Padua
Mattia Arboit: Medical School, University of Padua
Linda Diamante: University of Padova
Elena Carbognin: University of Padova
Patrizia Romani: Medical School, University of Padua
Federico La Torre: University of Padova
Elena Galimberti: University of Vienna, Vienna Biocenter
Florian Pflug: University of Vienna, Vienna Biocenter
Mirko Luoni: San Raffaele Scientific Institute
Serena Giannelli: San Raffaele Scientific Institute
Giuseppe Pepe: IRCCS Neuromed
Luca Capocci: IRCCS Neuromed
Alba Di Pardo: IRCCS Neuromed
Paola Vanzani: Medical School, University of Padua
Lucio Zennaro: Medical School, University of Padua
Vania Broccoli: San Raffaele Scientific Institute
Martin Leeb: University of Vienna, Vienna Biocenter
Enrico Moro: Medical School, University of Padua
Vittorio Maglione: IRCCS Neuromed
Graziano Martello: University of Padova

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39552-9

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