Abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Prior studies have highlighted the importance of AR nuclear localization in SBMA pathogenesis; therefore, in this study, we sought to determine the role of AR nuclear export in the pathological manifestations of SBMA. We demonstrate here that the nuclear export of polyQ-expanded AR is impaired, even prior to the formation of intranuclear inclusions of aggregated AR. Additionally, we find that promoting AR export with an exogenous nuclear export signal substantially reduces its aggregation and blocks hormone-induced toxicity. Moreover, we show that these protective effects are conferred by destabilization of the mutant protein due to an increase in proteasomal degradation of the cytoplasmic AR. Despite a growing body of evidence that global disruption of nucleo/cytoplasmic transport occurs in ALS and HD, our data suggest that no such global disruption occurs in models of SBMA; rather, AR-specific mechanisms, including reduced phosphorylation at Serine 650, are likely responsible for the impaired nuclear export of polyQ-expanded AR.
Highlights
The androgen receptor (AR) is a steroid hormone receptor that resides in the cytoplasm, in the absence of ligand, in an inactive aporeceptor complex that contains chaperones (Hsc[70], Hsp[40], Hsp[90], HIP, HOP), p23, and immunophilins (Cyp[40], FKBP51, FKBP52)[20,21]
A putative chromosomal maintenance 1 (CRM1) binding site was identified near the C-terminus of the AR, and the rapid nuclear export of AR that occurs upon inhibition of GSK-3β in prostate cancer cells is blocked by Leptomycin B29,30
This analysis revealed that, while AR10Q was evenly distributed between the PC12 and NIH/3T3 nuclei, AR112Q was retained to a greater extent within the PC12 nuclei, indicating deficient nuclear export of polyQ-expanded AR (Fig. 1A,B)
Summary
The AR is a steroid hormone receptor that resides in the cytoplasm, in the absence of ligand, in an inactive aporeceptor complex that contains chaperones (Hsc[70], Hsp[40], Hsp[90], HIP, HOP), p23, and immunophilins (Cyp[40], FKBP51, FKBP52)[20,21]. A putative CRM1 binding site was identified near the C-terminus of the AR, and the rapid nuclear export of AR that occurs upon inhibition of GSK-3β in prostate cancer cells is blocked by Leptomycin B29,30. Inhibition of JNK and p38 reduced the nuclear export of wildtype AR in COS-7 cells to an equivalent extent as a phospho-null (S650A) mutation but had no effect on AR with a phospho-mimic (S650D) mutation[34]. Consistent with these findings, knockdown of MAP3k11, an upstream regulator of JNK activity, decreased S650 phosphorylation in LNCaP and C2-4B cells[36]. Nuclear localization appears to play a key role in the pathogenesis of polyQ disease, with evidence for the therapeutic benefit of decreasing nuclear accumulation of some polyQ disease proteins
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