ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.

Abstract

Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.

• Authors: Zhiming Yang, Yu-Jia Chang, I-Chen Yu, Shuyuan Yeh, Cheng-Chia Wu, Hiroshi Miyamoto, Diane E Merry, Gen Sobue, Lu-Min Chen, Shu-Shi Chang, Chawnshang Chang
• Journal: Nature medicine (Nat Med) Vol. 13 Issue 3 Pg. 348-53 (Mar 2007) ISSN: 1078-8956 [Print] United States
• PMID: 17334372 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
• Androgen Receptor Antagonists
• Receptors, Androgen
• Curcumin

Topics

• Androgen Receptor Antagonists
• Animals
• COS Cells
• Cell Line
• Chlorocebus aethiops
• Curcumin (analogs & derivatives, therapeutic use)
• Disease Models, Animal
• Female
• Male
• Mice
• Mice, Transgenic
• Muscular Atrophy, Spinal (drug therapy, genetics, metabolism)
• Phenotype
• Receptors, Androgen (metabolism)