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

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

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.

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Authors
  • Ferlazzo, Giorgia Maria
  • Gambetta, Anna Maria
  • Amato, Sonia
  • Cannizzaro, Noemi
  • Angiolillo, Silvia
  • Arboit, Mattia
  • Diamante, Linda
  • Carbognin, Elena
  • Pflug, Florian G
  • Romani, Patrizia
  • La Torre, Federico
  • Galimberti, Elena
  • Capocci, Luca
  • Di Pardo, Alba
  • Vanzani, Paola
  • Zennaro, Lucio
  • Broccoli, Vania
  • Leeb, Martin
  • Moro, Enrico
  • Maglione, Vittorio
  • Martello, Graziano
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Shortfacts
Category
Journal Paper
Divisions
Bioinformatics and Computational Biology
Journal or Publication Title
Nature Communications
ISSN
2041-1723
Publisher
Springer Nature
Place of Publication
Headquarters location: London
Number
3962
Volume
14
Date
5 July 2023
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