Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease

• Published in: The Journal of clinical investigation 2015-02, Vol.125 (2), p.831-845
• Main Authors: Chua, Jason P, Reddy, Satya L, Yu, Zhigang, Giorgetti, Elisa, Montie, Heather L, Mukherjee, Sarmistha, Higgins, Jake, McEachin, Richard C, Robins, Diane M, Merry, Diane E, Iñiguez-Lluhí, Jorge A, Lieberman, Andrew P
• Format: Article
• Language: English
• Subjects: Animals; Biomedical research; Development and progression; Disease; Gene expression; Genetic aspects; Genetic transcription; Glutamine metabolism; Hypotheses; Kinases; Laboratory animals; Ligands; Mice; Mice, Transgenic; Muscle Fibers, Slow-Twitch - metabolism; Muscle Fibers, Slow-Twitch - pathology; Muscular Disorders, Atrophic - genetics; Muscular Disorders, Atrophic - metabolism; Muscular Disorders, Atrophic - pathology; Musculoskeletal system; Mutation; Neurodegeneration; Pathogenesis; PC12 Cells; Peptides - genetics; Peptides - metabolism; Physiological aspects; Principal components analysis; Proteins; Quality control; Rats; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Spinal muscular atrophy; Studies; Sumoylation; Transcription, Genetic
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci73214

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.