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

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.

• Authors: 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, Maria Pennuto
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 603 (02 06 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 36746939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2023. The Author(s).

Chemical References

• Receptors, Androgen
• Androgens
• Histone Demethylases

Topics

• Mice
• Animals
• Receptors, Androgen (genetics, metabolism)
• Bulbo-Spinal Atrophy, X-Linked (genetics)
• Androgens
• Diptera
• Gain of Function Mutation
• Phenotype
• Histone Demethylases (genetics)
• Muscular Disorders, Atrophic (genetics, metabolism)