Transcriptomics

Dataset Information

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Transcription profiling by array of Drosophila androgen receptor mutants


ABSTRACT: 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).

ORGANISM(S): Drosophila melanogaster  

SUBMITTER: Maria Pennuto  Jennifer Moore   Natalia B Nedelsky   Isabella Palazzolo   Zhiping Nie   Geoffrey Neale   J P Taylor   Rebecca B Smith   Geoffrey A Neale    

PROVIDER: E-GEOD-23802 | ArrayExpress | 2010-09-23

SECONDARY ACCESSION(S): GSE23802PRJNA130695

REPOSITORIES: GEO, ArrayExpress

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Publications

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

Nedelsky Natalia B NB   Pennuto Maria M   Smith Rebecca B RB   Palazzolo Isabella I   Moore Jennifer J   Nie Zhiping Z   Neale Geoffrey G   Taylor J Paul JP  

Neuron 20100901 6


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-depen  ...[more]

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