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

Nature Medicine volume 13, pages 348–353 (2007)Cite this article

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.

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Figure 1: ASC-J9 selectively promotes AR degradation by disrupting the interaction between AR and AR coregulators.
Figure 2: ASC-J9 suppresses the aggregation of AR-112Q in SBMA PC12/AR-112Q cells.
Figure 3: Effects of ASC-J9 (50 mg/kg every 48 h) on SBMA symptoms in male SBMA mice.
Figure 4: Effect of ASC-J9 (50 mg/kg every 48h) on the fertility and testosterone level of male SBMA mice.
Figure 5: ASC-J9 (50 mg/kg every 48h) treatment ameliorates neuromuscular pathological findings.
Figure 6: Molecular mechanisms of the effect of ASC-J9 on the SBMA phenotypes.

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Acknowledgements

We thank K. Wolf for help in editing the manuscript. This work was supported by US National Institutes of Health grant DK067686 and the George Whipple Professorship Endowment.

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Author notes

  1. Zhiming Yang and Yu-Jia Chang: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pathology, George Whipple Lab for Cancer Research, Urology, and Radiation Oncology, and The Cancer Center, University of Rochester Medical Center, Rochester, 14642, New York, USA

    Zhiming Yang, Yu-Jia Chang, I-Chen Yu, Shuyuan Yeh, Cheng-Chia Wu, Hiroshi Miyamoto, Lu-Min Chen, Shu-Shi Chang & Chawnshang Chang

  2. Zhejiang University and 2nd Hospital, Hangzhou, 310009, China

    Zhiming Yang

  3. Taipei Medical University and Hospital, Taipei, 110, Taiwan

    Yu-Jia Chang & Cheng-Chia Wu

  4. Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA

    Diane E Merry

  5. Nagoya University, Nagoya, 466-8550, Japan

    Gen Sobue

  6. China Medical University and Hospital, Taichung, 404, Taiwan

    Lu-Min Chen & Shu-Shi Chang

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  1. Zhiming Yang
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Correspondence to Chawnshang Chang.

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Competing interests

ASC-J9 was patented by the University of Rochester, the University of North Carolina and AndroScience Corporation, and then licensed to AndroScience Corporation. Both the University of Rochester and C.C. own royalty and equity in AndroScience Corporation.

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Yang, Z., Chang, YJ., Yu, IC. et al. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nat Med 13, 348–353 (2007). https://doi.org/10.1038/nm1547

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