Document Type
Article
Publication Date
1-15-2019
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.
Recommended Citation
Arnold, Frederick J.; Pluciennik, Anna; and Merry, Diane E., "Impaired Nuclear Export of Polyglutamine-Expanded Androgen Receptor in Spinal and Bulbar Muscular Atrophy." (2019). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 147.
https://jdc.jefferson.edu/bmpfp/147
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
30644418
Language
English
Comments
This article has been peer reviewed. It is the author’s final published version in Scientific Reports, Volume 9, Issue 1, January 2019, Article number 119.
The published version is available at https://doi.org/10.1038/s41598-018-36784-4. Copyright © Arnold et al.