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Human Expanded Polyglutamine Androgen Receptor Mutants in Neurodegeneration as a Novel Ligand Target
Androgen receptor (AR) plays key roles in various biological events, including pathological processes such as prostate cancer, androgen-insensitive syndrome, and spinal and bulbar muscular atrophy (SBMA). SBMA is caused by mutation of the expanded polyglutamine (polyQ) stretches in the AR gene. Rece...
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Published in: | The Journal of pharmacology and experimental therapeutics 2005-11, Vol.315 (2), p.545-552 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Androgen receptor (AR) plays key roles in various biological events, including pathological processes such as prostate cancer,
androgen-insensitive syndrome, and spinal and bulbar muscular atrophy (SBMA). SBMA is caused by mutation of the expanded polyglutamine
(polyQ) stretches in the AR gene. Recently, we established a Drosophila SBMA model that expresses the expanded polyQ hAR mutant in eyes, which monitors neurodegeneration as a rough eye phenotype.
In addition, we showed that androgen binding to the mutant hAR causes structural alterations, leading to the onset of neurodegeneration
in the fly eyes. In the present study, we examined whether the ligand-induced neurodegeneration via the hAR mutant is coupled
with the known ligand-induced transactivation function of hAR. By testing several known AR antagonists and several of their
structure-related compounds, we unexpectedly found that none of the AR ligands antagonized the hAR mutant neurodegeneration
function, and surprisingly, compound 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethylbenzonitrile (RU56279) was
more potent in inducing neurodegeneration. However, in vitro and in vivo mammalian assays showed that RU56279 exhibited the
expected antagonistic activity with the same potency as those of the other compounds. Thus, these findings suggest the presence
of a novel ligand-induced function of the polyQ hAR mutant in neurodegeneration that could not be prevented by known antagonists
for the hAR transactivation function. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.105.087643 |