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LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice

Author

Listed:
  • Ramachandran Prakasam

    (University of Trento)

  • Angela Bonadiman

    (University of Trento)

  • Roberta Andreotti

    (University of Padova
    Veneto Institute of Molecular Medicine
    Padova Neuroscience Center)

  • Emanuela Zuccaro

    (University of Padova
    Veneto Institute of Molecular Medicine
    Padova Neuroscience Center)

  • Davide Dalfovo

    (University of Trento)

  • Caterina Marchioretti

    (University of Padova
    Veneto Institute of Molecular Medicine
    Padova Neuroscience Center)

  • Debasmita Tripathy

    (University of Trento)

  • Gianluca Petris

    (University of Trento
    Medical Research Council Laboratory of Molecular Biology
    Wellcome Sanger Institute, Wellcome Trust Genome Campus)

  • Eric N. Anderson

    (University of Pittsburgh Medical Center)

  • Alice Migazzi

    (University of Trento
    University of Trento)

  • Laura Tosatto

    (University of Trento)

  • Anna Cereseto

    (University of Trento)

  • Elena Battaglioli

    (University of Milan)

  • Gianni Sorarù

    (Padova Neuroscience Center
    University of Padova)

  • Wooi Fang Lim

    (University of Oxford
    University of Oxford)

  • Carlo Rinaldi

    (University of Oxford
    University of Oxford)

  • Fabio Sambataro

    (Padova Neuroscience Center
    University of Padova)

  • Naemeh Pourshafie

    (National Institute of Neurological Disorders and Stroke, National Institutes of Health)

  • Christopher Grunseich

    (National Institute of Neurological Disorders and Stroke, National Institutes of Health)

  • Alessandro Romanel

    (University of Trento)

  • Udai Bhan Pandey

    (University of Pittsburgh Medical Center)

  • Andrea Contestabile

    (Istituto Italiano di Tecnologia)

  • Giuseppe Ronzitti

    (Université Paris-Saclay, Univ Evry, Inserm, Genethon
    Genethon)

  • Manuela Basso

    (University of Trento)

  • Maria Pennuto

    (University of Trento
    University of Padova
    Veneto Institute of Molecular Medicine
    Padova Neuroscience Center)

Abstract

Spinobulbar muscular atrophy (SBMA) is caused by CAG expansions in the androgen receptor gene. Androgen binding to polyQ-expanded androgen receptor triggers SBMA through a combination of toxic gain-of-function and loss-of-function mechanisms. Leveraging cell lines, mice, and patient-derived specimens, we show that androgen receptor co-regulators lysine-specific demethylase 1 (LSD1) and protein arginine methyltransferase 6 (PRMT6) are overexpressed in an androgen-dependent manner specifically in the skeletal muscle of SBMA patients and mice. LSD1 and PRMT6 cooperatively and synergistically transactivate androgen receptor, and their effect is enhanced by expanded polyQ. Pharmacological and genetic silencing of LSD1 and PRMT6 attenuates polyQ-expanded androgen receptor transactivation in SBMA cells and suppresses toxicity in SBMA flies, and a preclinical approach based on miRNA-mediated silencing of LSD1 and PRMT6 attenuates disease manifestations in SBMA mice. These observations suggest that targeting overexpressed co-regulators can attenuate androgen receptor toxic gain-of-function without exacerbating loss-of-function, highlighting a potential therapeutic strategy for patients with SBMA.

Suggested Citation

  • Ramachandran Prakasam & Angela Bonadiman & Roberta Andreotti & Emanuela Zuccaro & Davide Dalfovo & Caterina Marchioretti & Debasmita Tripathy & Gianluca Petris & Eric N. Anderson & Alice Migazzi & Lau, 2023. "LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36186-9
    DOI: 10.1038/s41467-023-36186-9
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    1. Qingshuang Cai & Rajesh Sahu & Vanessa Ueberschlag-Pitiot & Sirine Souali-Crespo & Céline Charvet & Ilyes Silem & Félicie Cottard & Tao Ye & Fatima Taleb & Eric Metzger & Roland Schuele & Isabelle M. , 2024. "LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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