A small-molecule activator of Hsf1, Nrf1, and Nrf2 mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy models (S34.006)

OBJECTIVE. To find a treatment for Spinal and bulbar muscular atrophy (SBMA). BACKGROUND. SBMA is an adult-onset neuromuscular disorder caused by the expansion of a CAG repeat in the androgen receptor (AR) gene, encoding a polyglutamine tract in the AR protein. Androgen binding to the polyglutamine-expanded AR promotes heat shock protein dissociation and nuclear translocation of the mutant protein, and these are important steps in the disease pathogenesis. In SBMA, as in other polyglutamine disorders, toxicity is primarily mediated by a toxic gain of function by the mutant protein and the consequent disruption of critical downstream pathways, including transcription, axonal transport, and mitochondrial function. No disease-specific treatment for SBMA is currently available. DESIGN. Here we tested the effects of a small molecule, the curcumin derivative ASC-JM17 in in vitro and in vivo models of SBMA. The compound was selected as candidate for further pharmacological development based on its efficacy in downregulating the levels of AR and its oral bioavailability. RESULTS. We found that ASC-JM17 effectively promotes degradation of polyglutamine-expanded AR protein, induces the HSF1-dependent heat shock response and enhances proteasomal activity through the Nrf1/NFE2L1 pathway. We also showed that ASC-JM17 is a strong inducer of the Nrf2/NFE2L2 antioxidant response pathway, which is a primary cellular defense against oxidative stress. Interestingly, the protective effect of ASC-JM17 in a Drosophila model of the disease was independent of HSF1 but required the Nrf1/2 ortholog CncC suggesting a central role for the proteasome and/or oxidative stress response. Additionally, treatment of a cohort of SBMA transgenic mice by oral administration also resulted in a significant amelioration of the phenotype and of the histological and biochemical alterations associated with the disease. CONCLUSIONS. Taken together, our results establish ASC-JM17 as a candidate for pharmacological intervention in SBMA and other neurodegenerative disorders. Disclosure: Dr. Rinaldi has nothing to disclose. Dr. Bott has nothing to disclose. Dr. Badders has nothing to disclose. Dr. Bautista has nothing to disclose. Dr. Harmison has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Taylor has nothing to disclose. Dr. Dantuma has nothing to disclose. Dr. Fischbeck has nothing to disclose.