Abstract |
Expansion of the polyglutamine ( polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA.
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Authors | Jason P Chua, Satya L Reddy, Zhigang Yu, Elisa Giorgetti, Heather L Montie, Sarmistha Mukherjee, Jake Higgins, Richard C McEachin, Diane M Robins, Diane E Merry, Jorge A Iñiguez-Lluhí, Andrew P Lieberman |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 125
Issue 2
Pg. 831-45
(Feb 2015)
ISSN: 1558-8238 [Electronic] United States |
PMID | 25607844
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Peptides
- Receptors, Androgen
- polyglutamine
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Topics |
- Animals
- Mice
- Mice, Transgenic
- Muscle Fibers, Slow-Twitch
(metabolism, pathology)
- Muscular Disorders, Atrophic
(genetics, metabolism, pathology)
- PC12 Cells
- Peptides
(genetics, metabolism)
- Rats
- Receptors, Androgen
(genetics, metabolism)
- Sumoylation
- Transcription, Genetic
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