Nature communications · 2023
Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity.
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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
Аннотация
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.