title: Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.
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.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Chua
authors.forename: Satya L
authors.initials: SL
authors.lastname: Reddy
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgetti
authors.forename: Heather L
authors.initials: HL
authors.lastname: Montie
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Jake
authors.initials: J
authors.lastname: Higgins
authors.forename: Richard C
authors.initials: RC
authors.lastname: McEachin
authors.forename: Diane M
authors.initials: DM
authors.lastname: Robins
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Iñiguez-Lluhí
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine