Spinobulbar muscular atrophy (SBMA) is a degenerative disorder of lower motor neurons caused by a CAG/glutamine expansion in the androgen receptor (AR) gene. The mutant protein (polyQ AR) undergoes hormone-dependent unfolding and oligomerization, steps that are critical to toxicity and to the development of progressive proximal limb and bulbar muscle weakness in men. Recent studies demonstrate that post- translational modifications of the AR triggered by ligand regulate toxicity. Specifically, conjugation of the polyQ AR by SUMO (small ubiquitin-like modifier) has been shown to impair ligand-dependent oligomerization of the mutant protein. However, the mechanism by which this occurs and the extent to which it alters the disease phenotype in vivo are currently unknown. The objective of this application is to determine how SUMOylation of the polyQ AR affects SBMA pathogenesis. The central hypothesis of this proposal is that SUMOylation promotes degradation of the polyQ AR and thereby limits accumulation of the misfolded protein and diminishes toxicity. This hypothesis springs from preliminary data demonstrating that SUMOylation decreases the levels of soluble AR oligomers in cellular models of SBMA.
In Aim 1, the extent to which SUMO Targeted Ubiquitin Ligases (STUbLs) degrade the SUMOylated polyQ AR will be delineated. This will be accomplished by stably expressing wild type and non-SUMOylatable AR mutants in an inducible cell model of SBMA and characterizing SUMO-mediated effect on STUbL recruitment, AR ubiquitination and degradation, and cell toxicity.
In Aim 2, the effects of SUMOylation will be characterized in a knock-in mouse model of SBMA. This will be accomplished by using gene targeting to generate SBMA knock-in mice that express a non- SUMOylatable polyQ AR. Analyses will then be performed to compare motor neuron degeneration and skeletal muscle pathology with that occurring in existing knock-in mice expressing a polyQ AR that is a target for SUMO. Successful completion of these aims is expected to define the mechanism underlying the protective effects of SUMO and allow for specific targeting of the SUMO pathway for therapeutic design.
The results of the proposed studies are expected to positively impact public health by defining the role of SUMO in protecting against motor neuron degeneration in spinobulbar muscular atrophy, thereby identifying potential therapeutic targets. As the mechanisms identified here are expected to regulate degradation of the androgen receptor (AR) at large, they will provide insights into the treatment of other AR-mediated diseases. Further, as several neurodegenerative disease-causing proteins are targeted by SUMO, these findings will serve as a paradigm for understanding how SUMOylation affects protein quality control and the phenotype of these related disorders.
| Chua, Jason P; Reddy, Satya L; Yu, Zhigang et al. (2015) Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease. J Clin Invest 125:831-45 |
| Renier, Kayla J; Troxell-Smith, Sandra M; Johansen, Jamie A et al. (2014) Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy. Endocrinology 155:2624-34 |
| Chua, Jason P; Reddy, Satya L; Merry, Diane E et al. (2014) Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy. Hum Mol Genet 23:1376-86 |
| Wang, Adrienne M; Miyata, Yoshinari; Klinedinst, Susan et al. (2013) Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 9:112-8 |
| Chua, Jason P; Lieberman, Andrew P (2013) Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy. CNS Neurol Disord Drug Targets 12:1146-56 |
