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- Title
Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity.
- Authors
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
- 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.Huntington’s disease is caused by mutation in the HTT gene. Here, the authors screen for suppressors of mutant HTT-induced toxicity, identifying Mtf1. Mtf1 reduced oxidative stress and cell death in stem cells, and motor defects and protein aggregates in mouse models.
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-39552-9