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Citations to this article

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated disease
Jason P. Chua, … , Jorge A. Iñiguez-Lluhí, Andrew P. Lieberman
Jason P. Chua, … , Jorge A. Iñiguez-Lluhí, Andrew P. Lieberman
Published January 20, 2015
Citation Information: J Clin Invest. 2015;125(2):831-845. https://doi.org/10.1172/JCI73214.
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Research Article Article has an altmetric score of 3

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

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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

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

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Total citations by year

Year: 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2009 Total
Citations: 2 1 3 2 1 7 3 2 3 7 1 32
Citation information
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Citations to this article (32)

Title and authors Publication Year
Energy metabolism is differentially disrupted in spinal cord and muscle in spinal and bulbar muscular atrophy
Danielle DeBartolo, Frederick J. Arnold, Yuhong Liu, Elana Molotsky, Hsin-Yao Tang, Diane Merry
JCI Insight 2024
Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA
Karliner J, Liu Y, Merry DE
Proceedings of the National Academy of Sciences 2024
Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates?
Cheng X, Yang W, Lin W, Mei F
Pharmacological reviews 2023
GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression
G Addicks, H Zhang, D Ryu, G Vasam, A Green, P Marshall, S Patel, B Kang, D Kim, E Katsyuba, E Williams, J Renaud, J Auwerx, K Menzies
The Journal of Cell Biology 2022
Exploring the Role of Posttranslational Modifications in Spinal and Bulbar Muscular Atrophy
Gogia N, Ni L, Olmos V, Haidery F, Luttik K, Lim J
Frontiers in molecular neuroscience 2022
The CARM1 transcriptome and arginine methylproteome mediate skeletal muscle integrative biology.
vanLieshout TL, Stouth DW, Hartel NG, Vasam G, Ng SY, Webb EK, Rebalka IA, Mikhail AI, Graham NA, Menzies KJ, Hawke TJ, Ljubicic V
Molecular Metabolism 2022
Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy
Anna Pluciennik, Yuhong Liu, Elana Molotsky, Gregory B. Marsh, Bedri Ranxhi, Frederick J. Arnold, Sophie St-Cyr, Beverly L. Davidson, Naemeh Pourshafie, Andrew P. Lieberman, Wei Gu, Sokol V. Todi, Diane E Merry
Journal of Clinical Investigation 2021
Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity
WF Lim, M Forouhan, TC Roberts, J Dabney, R Ellerington, AA Speciale, R Manzano, M Lieto, G Sangha, S Banerjee, M Conceição, L Cravo, A Biscans, L Roux, N Pourshafie, C Grunseich, S Duguez, A Khvorova, M Pennuto, CJ Cortes, AR Spada, KH Fischbeck, MJ Wood, C Rinaldi
Science Advances 2021
MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease
SR Nath, ML Lieberman, Z Yu, C Marchioretti, ST Jones, EC Danby, KM Pelt, G Sorarù, DM Robins, GP Bates, M Pennuto, AP Lieberman
Acta Neuropathologica 2020
Impaired Nuclear Export of Polyglutamine-Expanded Androgen Receptor in Spinal and Bulbar Muscular Atrophy
FJ Arnold, A Pluciennik, DE Merry
Scientific Reports 2019
Polyglutamine Repeats in Neurodegenerative Diseases
AP Lieberman, VG Shakkottai, RL Albin
Annual review of pathology 2019
Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction
FP Zhang, M Malinen, A Mehmood, T Lehtiniemi, T Jääskeläinen, EA Niskanen, H Korhonen, A Laiho, LL Elo, C Ohlsson, N Kotaja, M Poutanen, P Sipilä, JJ Palvimo
Nature Communications 2019
Humanising the mouse genome piece by piece
F Zhu, RR Nair, EM Fisher, TJ Cunningham
Nature Communications 2019
Molecular Mechanisms and Therapeutics for SBMA/Kennedy’s Disease
FJ Arnold, DE Merry
Neurotherapeutics 2019
Targeting AR-Beclin 1 complex-modulated growth factor signaling increases the antiandrogen Enzalutamide sensitivity to better suppress the castration-resistant prostate cancer growth
M Zhang, Y Sun, J Meng, L Zhang, C Liang, C Chang
Cancer Letters 2019
The first year
J Attems
Acta Neuropathologica 2019
Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction
Samir R Nath, Zhigang Yu, Theresa A Gipson, Gregory B Marsh, Eriko Yoshidome, Diane M Robins, Sokol V. Todi, David Housman, Andrew P. Lieberman
Journal of Clinical Investigation 2018
Transcriptional Dysregulation and Post-translational Modifications in Polyglutamine Diseases: From Pathogenesis to Potential Therapeutic Strategies
C Xiang, S Zhang, X Dong, S Ma, S Cong
Frontiers in molecular neuroscience 2018
SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models
M Marinello, A Werner, M Giannone, K Tahiri, S Alves, C Tesson, W den Dunnen, JS Seeler, A Brice, A Sittler
Disease models & mechanisms 2018
Post-translational Modifications and Protein Quality Control in Motor Neuron and Polyglutamine Diseases
F Sambataro, M Pennuto
Frontiers in molecular neuroscience 2017
Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases
R Cristofani, V Crippa, P Rusmini, ME Cicardi, M Meroni, NV Licata, G Sala, E Giorgetti, C Grunseich, M Galbiati, M Piccolella, E Messi, C Ferrarese, S Carra, A Poletti
Autophagy 2017
Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing
E Giorgetti, Z Yu, JP Chua, R Shimamura, L Zhao, F Zhu, S Venneti, M Pennuto, Y Guan, G Hung, AP Lieberman
Cell Reports 2016
Ubiquitin-dependent and independent roles of SUMO in proteostasis
F Liebelt, AC Vertegaal
American journal of physiology. Cell physiology 2016
Polyglutamine androgen receptor-mediated neuromuscular disease
E Giorgetti, AP Lieberman
Cellular and Molecular Life Sciences 2016
Fighting polyglutamine disease by wrestling with SUMO
Tim Craig, Jeremy Henley
Journal of Clinical Investigation 2015
The polyglutamine-expanded androgen receptor has increased DNA binding and reduced transcriptional activity
S Belikov, LC Bott, KH Fischbeck, Ö Wrange
Biochemistry and Biophysics Reports 2015
Trinucleotide repeats and protein folding and disease: the perspective from studies with the androgen receptor
FA Orafidiya, IJ McEwan
Future Science OA 2015
Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
P Rusmini, MJ Polanco, R Cristofani, ME Cicardi, M Meroni, M Galbiati, M Piccolella, E Messi, E Giorgetti, AP Lieberman, C Milioto, A Rocchi, T Aggarwal, M Pennuto, V Crippa, A Poletti
Scientific Reports 2015
Targeted Molecular Therapies for SBMA
C Rinaldi, B Malik, L Greensmith
Journal of Molecular Neuroscience 2015
Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA
L Zboray, A Pluciennik, D Curtis, Y Liu, LD Berman-Booty, C Orr, CT Kesler, T Berger, D Gioeli, BM Paschal, DE Merry
Cell Reports 2015
Undoing SUMO aids polyQ AR
Lieberman AP, Iniguez-Lluhi JA
Oncotarget 2015
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2009

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