An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy

Shannon C. Jenkins,Heather L. Montie,Elizabeth M. Wilson,Christopher R. Orr,James D. Joseph,Donald P. McDonnell,Diane E. Merry,Yuhong Liu,Elena Bolzoni

doi:10.1074/jbc.m110.146845

Abstract

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.

Highlights

Expanded polyglutamine tract within the androgen receptor (AR) leads to its misfolding, aberrant cleavage, and accumulation [4, 5], how these phenomena lead to neuronal dysfunction and death is unclear
These data indicate that the interdomain N/C interaction is required for phosphorylation of serines 81 and 308 and that these post-translational modifications can be used to report on the N/C interaction. The roles of both hormone binding and nuclear localization of the mutant, polyglutamine-expanded AR have been established as essential components of the pathogenic process in spinal and bulbar muscular atrophy (SBMA) (8 –11, 31)
Our studies presented here focused on this question, in an effort to identify upstream steps in the pathogenic process that can be targeted for therapeutic benefit

Summary

Introduction

Expanded polyglutamine tract within the AR leads to its misfolding, aberrant cleavage, and accumulation [4, 5], how these phenomena lead to neuronal dysfunction and death is unclear. Treatment of NLSX3-AR76Q-expressing cells with bicalutamide resulted in a substantial reduction of the number of cells with nuclear inclusions compared to treatment with DHT (Fig. 1D), indicating that bicalutamide inhibits mutant AR aggregation and toxicity independently of any potential effect on nuclear translocation.

Results

Conclusion