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AR function is altered by polyglutamine expansion and by SUMO

ABSTRACT: Expansion of a polyglutamine (polyQ) tract in the gene for the androgen receptor (AR) results in partial loss of transactivation function and causes spinobulbar muscular atrophy (SBMA). Modification of AR by small ubiquitin-like modifier (SUMO) reduces AR function in a promoter context-dependent manner. We used microarrays to confirm and demonstrate loss of AR function from polyQ expansion and to test the degree to which AR function is altered by preventing polyQ AR SUMOylation.

ORGANISM(S): Mus musculus Rattus norvegicus

PROVIDER: GSE50383 | GEO | 2014/08/23

SECONDARY ACCESSION(S): PRJNA217371

REPOSITORIES: GEO

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AR function is altered by polyglutamine expansion and by SUMO

Project description:Expansion of a polyglutamine (polyQ) tract in the gene for the androgen receptor (AR) results in partial loss of transactivation function and causes spinobulbar muscular atrophy (SBMA). Modification of AR by small ubiquitin-like modifier (SUMO) reduces AR function in a promoter context-dependent manner. We used microarrays to confirm and demonstrate loss of AR function from polyQ expansion and to test the degree to which AR function is altered by preventing polyQ AR SUMOylation. PC12 cells expressing AR10Q, AR112Q, or nonSUMOylatable AR112Q (KRKR) in the presence or absence of synthetic androgen R1881 were assessed for alterations in AR function by comparing gene expression changes with each AR variant in response to ligand.

2014-08-23 | E-GEOD-50383 | biostudies-arrayexpress

Disrupting SUMOylation potentiates transactivation function and ameliorates polyglutamine AR-mediated disease

Project description:Our findings demonstrate beneficial effects of enhancing transactivation function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may provide new targets for therapeutic intervention. We mutated conserved lysines in the polyQ AR that are targeted by SUMO, a modification that inhibits AR transactivation function.

2015-12-21 | E-GEOD-60691 | biostudies-arrayexpress

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

Project description:Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite outgrowth, induced neurite retraction, and inhibited neurite regrowth. This dysfunction was independent of polyQ-expanded AR transcriptional activity at androgen response elements (AREs). We further showed that the formation of polyQ-expanded AR intranuclear inclusions promoted neurite retraction, which coincided with reduced expression of the neuronal differentiation marker -III-Tubulin. Finally, we revealed that cell death is not the primary outcome for cells undergoing neurite retraction; rather, these cells become senescent. Our findings reveal that mechanisms independent of AR canonical transcriptional activity underly neurite defects in a cell model of SBMA and identify senescence as a previously unappreciated pathway implicated in this pathology. These findings suggest that, in the absence of a role for AR canonical transcriptional activity in the SBMA pathologies described here, the development of SBMA therapeutics that preserve this activity may be desirable. This approach may be broadly applicable to other polyglutamine diseases such as Huntington’s disease and spinocerebellar ataxias.

2024-07-05 | GSE267802 | GEO

Disrupting SUMOylation potentiates transactivation function and ameliorates polyglutamine AR-mediated disease

2015-12-21 | GSE60691 | GEO

Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy

Project description:Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary but not sufficient for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases. We used Affymetrix arrays to generate a molecular phenotype of degeneration in profile flies expressing wild-type or polyglutamine-expanded AR. We also expressed in the fly eye polyglutamine-expanded AR with point mutations affecting the DNA binding domain and the AF-2 domain. In some experiments, GMR-GAL4; UAR-AR flies were crossed to flies carrying a chromosomal duplication of the limpet gene. Transgene expression was induced in the eye using GMR-GAL4. Flies were crossed at 29 deg C on food containing either 1mM DHT or 1% ethanol (vehicle).

2010-09-23 | E-GEOD-23802 | biostudies-arrayexpress

Transcriptomic profiling of spinal and bulbar muscular atrophy cultured embryonic motor neurons

Project description:Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, is a slowly progressive adult-onset neuromuscular disease which results from a polyglutamine (polyQ) encoding CAG repeat expansion within the androgen receptor gene (AR). Despite the ubiquitous expression of the androgen receptor, it is unclear why motor neurons selectively degenerate and there are no effective treatments or disease modifying therapies for this debilitating disease. In order to identify potential therapeutic targets, we set out to establish the genes and molecular pathways involved in early motor neuron dysfunction in SBMA. We therefore undertook global transcriptomic profiling of cultured primary embryonic motor neurons from the spinal cord of AR100 mice, which model SBMA.. Four biological replicate samples were used for genome wide analysis using Affymetrix 430 v2.0 mouse arrays. Data was normalised using therobust multichip average (RMA) algorithm.

2019-05-02 | E-MTAB-6986 | biostudies-arrayexpress

Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy

2010-09-23 | GSE23802 | GEO

Rattus norvegicus

Project description:AR function is altered by polyglutamine expansion and by SUMO

| PRJNA217371 | ENA

ANDROGEN RECEPTOR WITH SHORT POLYGLUTAMINE TRACT PREFERABLY ENHANCES WNT/BETA-CATENIN MEDIATED PROSTATE TUMORIGENESIS

Project description:Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we investigated aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of b-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized b-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/b-catenin in combination with short polyQ AR expression in prostate tumorigenesis and provide mechanistic insight into aggressive prostatic tumor development that is frequently observed in African American patients.

2020-03-31 | GSE140963 | GEO

Effects of polyglutamine expansion and subcellular localization of C-terminal fragment of Cav2.1 in PC12 rat pheochromocytoma cells

Project description:Polyglutamine(polyQ) expansion of α1A voltage-dependent calcium channel (Cav2.1) is the causative mutation of spinocerebellar ataxia type 6 (SCA6). The C-terminal fragment (CTF) of Cav2.1 makes aggregates in the cytoplasm of SCA6 Purkinje cells and may relate to the pathogenesis. In order to identify genes associated with polyQ expansion and subcellular localization of CTF, we analyzed gene expression profiles of PC12 rat pheochromocytoma cells using Tet-off system.

2013-03-13 | GSE26933 | GEO

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