Testing Synthetic Curcumin Analogs as Potential Treatments for Kennedy's Disease

Ruicong Zhong

Ruicong Zhong
Columbia University (New York)

Fischbeck Lab

Preceptors: Laura Bott, Carlo Rinaldi, Kurt Fischbeck


Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a genetic neuromuscular disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Acurcumin-related compound has been found to counteract the toxicity of mutant AR in the SBMA mouse model by reducing AR protein levels. Using cellular and transgenic mouse models of SBMA, we aimed to test the effects and investigate the mechanisms of action of two orally activecurcuminanalogs, ASC-J9 and ASC-JM17. By western blot analysis, we showed thatASC-J9 and ASC-JM17 reduced the levels of AR in fibroblast cells derived from SBMA patients and in muscle lysates from transgenic SBMA mice. We further showed that ASC-J9 and ASC-JM17 are able to activate the Nrf2 pathway in cultured cells and increase the expression of an Nrf2 downstream target, HO-1, in a concentration-dependent manner. Also, we found that ASC-JM17 is more potent than ASC-J9 both in reducing the levels of AR and in promoting the expression of HO-1. Our results support the development of curcumin analogs as a treatment for SBMA.