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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.
Prakasam, Ramachandran; Bonadiman, Angela; Andreotti, Roberta; Zuccaro, Emanuela; Dalfovo, Davide; Marchioretti, Caterina; Tripathy, Debasmita; Petris, Gianluca; Anderson, Eric N; Migazzi, Alice; Tosatto, Laura; Cereseto, Anna; Battaglioli, Elena; Sorarù, Gianni; Lim, Wooi Fang; Rinaldi, Carlo; Sambataro, Fabio; Pourshafie, Naemeh; Grunseich, Christopher; Romanel, Alessandro; Pandey, Udai Bhan; Contestabile, Andrea; Ronzitti, Giuseppe; Basso, Manuela; Pennuto, Maria.
Afiliação
  • Prakasam R; Dulbecco Telethon Institute at the Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Bonadiman A; Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Andreotti R; Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • Zuccaro E; Veneto Institute of Molecular Medicine, Padova, Italy.
  • Dalfovo D; Padova Neuroscience Center, Padova, Italy.
  • Marchioretti C; Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • Tripathy D; Veneto Institute of Molecular Medicine, Padova, Italy.
  • Petris G; Padova Neuroscience Center, Padova, Italy.
  • Anderson EN; Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Migazzi A; Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • Tosatto L; Veneto Institute of Molecular Medicine, Padova, Italy.
  • Cereseto A; Padova Neuroscience Center, Padova, Italy.
  • Battaglioli E; Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Sorarù G; Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Lim WF; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
  • Rinaldi C; Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden, UK.
  • Sambataro F; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Pourshafie N; Dulbecco Telethon Institute at the Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Grunseich C; Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Romanel A; Dulbecco Telethon Institute at the Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Pandey UB; Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
  • Contestabile A; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
  • Ronzitti G; Padova Neuroscience Center, Padova, Italy.
  • Basso M; Department of Neuroscience, University of Padova, Padova, Italy.
  • Pennuto M; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK.
Nat Commun ; 14(1): 603, 2023 02 06.
Article em En | MEDLINE | ID: mdl-36746939
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos Musculares Atróficos / Dípteros / Atrofia Bulboespinal Ligada ao X Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos Musculares Atróficos / Dípteros / Atrofia Bulboespinal Ligada ao X Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article