IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-39552-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-39552-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-39552-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Zengpeng Han & Nengsong Luo & Wenyu Ma & Xiaodong Liu & Yuxiang Cai & Jiaxin Kou & Jie Wang & Lei Li & Siqi Peng & Zihong Xu & Wen Zhang & Yuxiang Qiu & Yang Wu & Chaohui Ye & Kunzhang Lin & Fuqiang X, 2023. "AAV11 enables efficient retrograde targeting of projection neurons and enhances astrocyte-directed transduction," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Irene Molina-Gonzalez & Rebecca K. Holloway & Zoeb Jiwaji & Owen Dando & Sarah A. Kent & Katie Emelianova & Amy F. Lloyd & Lindsey H. Forbes & Ayisha Mahmood & Thomas Skripuletz & Viktoria Gudi & Jame, 2023. "Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39552-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.