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

Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2010; 285(46):35567-77. DOI: 10.1074/jbc.M110.146845
Source: PubMed


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.

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    • "the AR, were tested in a cell model of SBMA and motor neurons from transgenic AR112Q mice (Orr et al., 2010). Bicalutamide not only decreased polyQ AR N/C-terminal interactions, but reduced nuclear inclusion formation in PC12 cells expressing AR112Q, even in the presence of DHT. "
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    ABSTRACT: Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA.
    Full-text · Article · May 2013 · Frontiers in Neurology
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    • "The antiandrogen bicalutamide, which also targets the N/C interaction, has been shown to reduce polyQ-AR aggregation and prevent androgen-dependent toxicity in PC12 cells expressing polyQ-AR and in primary motor neurons obtained from SBMA mice (Orr et al. 2010). Other selective AR modulators (SARMs) that inhibit the AR N/C interaction, such as the two SARMs RTI-016 and RTI-051b, also reduce aggregation and toxicity, further supporting the relevance of this conformational change in SBMA pathogenesis (Orr et al. 2010). "
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    ABSTRACT: Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a genetically inherited neuromuscular disorder characterized by loss of lower motor neurons in the brainstem and spinal cord and skeletal muscle fasciculation, weakness, and atrophy. SBMA is caused by expansion of a polyglutamine (polyQ) tract in the gene coding for the androgen receptor (AR). PolyQ expansions cause at least eight other neurological disorders, which are collectively known as polyQ diseases. SBMA is unique in the family of polyQ diseases in that the disease manifests fully in male individuals only. The sex specificity of SBMA is the result of the interaction between mutant AR and its natural ligand, testosterone. Here, we will discuss emerging therapeutic perspectives for SBMA in light of recent findings regarding disease pathogenesis.
    Full-text · Article · Feb 2013 · Journal of Molecular Neuroscience
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    • "This N/C interaction is critical for toxicity through stabilizing the AR and enhancing hormone binding [44] [45]. Selective androgen receptor modulators such as RTI-016 and RTI- 051b prevent the N/C interaction and ameliorated AR aggregation and toxicity while retaining AR transcriptional function, highlighting a novel therapeutic strategy for SBMA (Figure 1) [45]. Another strategy for reducing toxicity of mutant AR is based on alteration of the morphology of the oligomers. "
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    ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss in the spinal cord and brainstem. Androgen receptor (AR), a disease-causing protein of SBMA, is a well-characterized ligand-activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted for conformational changes of AR including amino-terminal (N) and carboxy-terminal (C) (N/C) interaction and transcriptional coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS), and autophagy could be applicable for all types of polyglutamine diseases.
    Full-text · Article · Jun 2012 · Neural Plasticity
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