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

Ramachandran Prakasam, Angela Bonadiman, Roberta Andreotti, Emanuela Zuccaro, Davide Dalfovo, Caterina Marchioretti, Debasmita Tripathy, Gianluca Petris, Eric N. Anderson, Alice Migazzi, Laura Tosatto, Anna Cereseto, Elena Battaglioli, Gianni Sorarù, Wooi Fang Lim, Carlo Rinaldi, Fabio Sambataro, Naemeh Pourshafie, Christopher Grunseich, Alessandro Romanel, Udai Bhan Pandey, Andrea Contestabile, Giuseppe Ronzitti, Manuela Basso () and Maria Pennuto ()
Additional contact information
Ramachandran Prakasam: University of Trento
Angela Bonadiman: University of Trento
Roberta Andreotti: University of Padova
Emanuela Zuccaro: University of Padova
Davide Dalfovo: University of Trento
Caterina Marchioretti: University of Padova
Debasmita Tripathy: University of Trento
Gianluca Petris: University of Trento
Eric N. Anderson: University of Pittsburgh Medical Center
Alice Migazzi: University of Trento
Laura Tosatto: University of Trento
Anna Cereseto: University of Trento
Elena Battaglioli: University of Milan
Gianni Sorarù: Padova Neuroscience Center
Wooi Fang Lim: University of Oxford
Carlo Rinaldi: University of Oxford
Fabio Sambataro: Padova Neuroscience Center
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
Manuela Basso: University of Trento
Maria Pennuto: University of Trento

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36186-9

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