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

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

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)348-353
Number of pages6
JournalNature medicine
Issue number3
StatePublished - Mar 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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