A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy.
Bott LC., Badders NM., Chen KL., Harmison GG., Bautista E., Shih CC., Katsuno M., Sobue G., Taylor JP., Dantuma NP., Fischbeck KH., Rinaldi C.
Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation, and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2, and Hsf1, to increase the expression of proteasome subunits, antioxidant enzymes, and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly, and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog CncC, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.