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

Author

Listed:
  • Giorgia Maria Ferlazzo

    (Medical School, University of Padua
    an Evotec Company, Campus Levi-Montalcini)

  • Anna Maria Gambetta

    (Medical School, University of Padua
    University of Padova)

  • Sonia Amato

    (University of Padova
    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
    CNR Institute of Neuroscience)

  • Martin Leeb

    (University of Vienna, Vienna Biocenter)

  • Enrico Moro

    (Medical School, University of Padua)

  • Vittorio Maglione

    (IRCCS Neuromed)

  • Graziano Martello

    (University of Padova)

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.

Suggested Citation

  • Giorgia Maria Ferlazzo & Anna Maria Gambetta & Sonia Amato & Noemi Cannizzaro & Silvia Angiolillo & Mattia Arboit & Linda Diamante & Elena Carbognin & Patrizia Romani & Federico La Torre & Elena Galim, 2023. "Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39552-9
    DOI: 10.1038/s41467-023-39552-9
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    References listed on IDEAS

    as
    1. Zheng Wu & Matthew Parry & Xiao-Yi Hou & Min-Hui Liu & Hui Wang & Rachel Cain & Zi-Fei Pei & Yu-Chen Chen & Zi-Yuan Guo & Sambangi Abhijeet & Gong Chen, 2020. "Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    2. Irene Zorzan & Marco Pellegrini & Mattia Arboit & Danny Incarnato & Mara Maldotti & Mattia Forcato & Guidantonio Malagoli Tagliazucchi & Elena Carbognin & Marco Montagner & Salvatore Oliviero & Grazia, 2020. "The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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