ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.
Publication/Presentation Date
3-1-2007
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.
Volume
13
Issue
3
First Page
348
Last Page
353
ISSN
1078-8956
Published In/Presented At
Yang, Z., Chang, Y. J., Yu, I. C., Yeh, S., Wu, C. C., Miyamoto, H., Merry, D. E., Sobue, G., Chen, L. M., Chang, S. S., & Chang, C. (2007). ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nature medicine, 13(3), 348–353. https://doi.org/10.1038/nm1547
Disciplines
Medicine and Health Sciences
PubMedID
17334372
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article