Kennedy’s disease: targeting LSD1 and PRMT6 overexpression attenuates mutated androgen receptor toxicity without worsening androgen deficiency

Lysine-specific demethylase 1 (LSD1) and protein arginine N-methyltransferase 6 (PRMT6) are co-regulators of the androgen receptor.

• Overexpressed by androgens specifically in skeletal muscle of mice and humans with Kennedy’s disease (SBMA), these molecules synergistically activate the androgen receptor, this activation being enhanced by polyQ expansions.
• Pharmacological silencing of LSD1 and PRMT6 attenuates the activation of abnormal androgen receptors and suppresses their toxicity in model flies.
• Administration of a miRNA silencing LSD1 and PRMT6 decreases the manifestations of SBMA in a mouse model.

 

LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice.Prakasam R, Bonadiman A, Andreotti R, et al. Nat Commun. 2023 Feb 6;14(1):603.