Spinal and bulbar muscular atrophy (SBMA) is caused by CAG repeat expansions in the androgen receptor (AR) gene.
Binding of androgens to the polyglutamine-expanded (polyQ) AR triggers SBMA through a combination of toxic gain-of-function and loss-of-function mechanisms.
Using cell lines, mouse models, and patient-derived samples, we demonstrate that the AR co-regulators lysine-specific demethylase 1 (LSD1) and protein arginine methyltransferase 6 (PRMT6) are overexpressed in an androgen-dependent manner specifically in the skeletal muscles of SBMA patients and mice. LSD1 and PRMT6 cooperate to synergistically transactivate the AR, and this effect is enhanced by the polyglutamine expansion.
Pharmacological and genetic silencing of LSD1 and PRMT6 reduces transactivation of the expanded AR in SBMA cells and suppresses toxicity in SBMA Drosophila models. Moreover, a preclinical approach based on miRNA-mediated silencing of LSD1 and PRMT6 alleviates disease manifestations in SBMA mice.
These findings suggest that targeting overexpressed AR co-regulators can mitigate the toxic gain-of-function effects of the mutant receptor without exacerbating loss of function, highlighting a promising therapeutic strategy for SBMA patients.
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