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 journalArticle

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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.

Original languageEnglish
Pages (from-to)348-353
Number of pages6
JournalNature Medicine
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2007

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Atrophic Muscular Disorders
Androgen Receptors
Phenotype
Degradation
Agglomeration
X-Linked Bulbo-Spinal Atrophy
Cells
Nerve Degeneration
Muscular Atrophy
Castration
Motor Neurons
Intraperitoneal Injections
Transgenic Mice
Neurons
Fertility
Testosterone
Cultured Cells
Cell Survival
polyglutamine
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. / Yang, Zhiming; Chang, Yu Jia; Yu, I. Chen; Yeh, Shuyuan; Wu, Cheng Chia; Miyamoto, Hiroshi; Merry, Diane E.; Sobue, Gen; Chen, Lu Min; Chang, Shu Shi; Chang, Chawnshang.

In: Nature Medicine, Vol. 13, No. 3, 03.2007, p. 348-353.

Research output: Contribution to journalArticle

Yang, Z, Chang, YJ, Yu, IC, Yeh, S, Wu, CC, Miyamoto, H, Merry, DE, Sobue, G, Chen, LM, Chang, SS & Chang, C 2007, 'ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor', Nature Medicine, vol. 13, no. 3, pp. 348-353. https://doi.org/10.1038/nm1547
Yang, Zhiming ; Chang, Yu Jia ; Yu, I. Chen ; Yeh, Shuyuan ; Wu, Cheng Chia ; Miyamoto, Hiroshi ; Merry, Diane E. ; Sobue, Gen ; Chen, Lu Min ; Chang, Shu Shi ; Chang, Chawnshang. / ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. In: Nature Medicine. 2007 ; Vol. 13, No. 3. pp. 348-353.
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