Journal of Biological Chemistry
Volume 285, Issue 46, November 2010, Pages 35567-35577
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Molecular Bases of Disease
An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy*

https://doi.org/10.1074/jbc.M110.146845Get rights and content
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Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5α-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5α-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function.

Neurodegeneration
Polyglutamine Disease
Protein Folding
Protein Motifs
Protein Phosphorylation
Androgen Receptor
Motor Neuron Disease

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*

This work was supported, in whole or in part, by National Institutes of Health Grants R01 NS32214 (to D. E. M.), DK07705 (to H. L. M.), CA139818 (to D. P. M.), and HD16910 (to E. M. W.).