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| Status |
Public on Sep 23, 2010 |
| Title |
Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy |
| Organism |
Drosophila melanogaster |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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).
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| Contributor(s) |
Nedelsky NB, Pennuto M, Smith RB, Palazzolo I, Moore J, Nie Z, Neale GA, Taylor JP |
| Citation(s) |
20869592 |
| Submission date |
Aug 25, 2010 |
| Last update date |
Aug 28, 2018 |
| Contact name |
Geoffrey Neale |
| E-mail(s) |
geoffrey.neale@stjude.org
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| Organization name |
St Jude Childrens Research Hospital
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| Department |
Hartwell Center
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| Street address |
262 Danny Thomas Place
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (1) |
| GPL1322 |
[Drosophila_2] Affymetrix Drosophila Genome 2.0 Array |
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| Samples (54)
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| GSM587040 |
AR12Q, vehicle-treated, replicate 1 |
| GSM587041 |
AR12Q, vehicle-treated, replicate 2 |
| GSM587042 |
AR12Q, vehicle-treated, replicate 3 |
| GSM587043 |
AR12Q, vehicle-treated, replicate 4 |
| GSM587044 |
AR12Q, DHT-treated, replicate 1 |
| GSM587045 |
AR12Q, DHT-treated, replicate 2 |
| GSM587046 |
AR12Q, DHT-treated, replicate 3 |
| GSM587047 |
AR12Q, DHT-treated, replicate 4 |
| GSM587048 |
AR52Q, vehicle-treated, replicate 1 |
| GSM587049 |
AR52Q, vehicle-treated, replicate 2 |
| GSM587050 |
AR52Q, vehicle-treated, replicate 3 |
| GSM587051 |
AR52Q, vehicle-treated, replicate 4 |
| GSM587052 |
AR52Q, DHT-treated, replicate 1 |
| GSM587053 |
AR52Q, DHT-treated, replicate 2 |
| GSM587054 |
AR52Q, DHT-treated, replicate 3 |
| GSM587055 |
AR52Q, DHT-treated, replicate 4 |
| GSM587056 |
AR66Q E897K, vehicle-treated, replicate 1 |
| GSM587057 |
AR66Q E897K, vehicle-treated, replicate 2 |
| GSM587058 |
AR66Q E897K, vehicle-treated, replicate 3 |
| GSM587059 |
AR66Q E897K, vehicle-treated, replicate 4 |
| GSM587060 |
AR66Q E897K, DHT-treated, replicate 1 |
| GSM587061 |
AR66Q E897K, DHT-treated, replicate 2 |
| GSM587062 |
AR66Q E897K, DHT-treated, replicate 3 |
| GSM587063 |
AR72Q K720A, vehicle-treated, replicate 1 |
| GSM587064 |
AR72Q K720A, vehicle-treated, replicate 2 |
| GSM587065 |
AR72Q K720A, vehicle-treated, replicate 3 |
| GSM587066 |
AR72Q K720A, vehicle-treated, replicate 4 |
| GSM587067 |
AR72Q K720A, DHT-treated, replicate 1 |
| GSM587068 |
AR72Q K720A, DHT-treated, replicate 2 |
| GSM587069 |
AR72Q K720A, DHT-treated, replicate 3 |
| GSM587070 |
AR72Q K720A, DHT-treated, replicate 4 |
| GSM587071 |
AR52Q A574D, vehicle-treated, replicate 1 |
| GSM587072 |
AR52Q A574D, vehicle-treated, replicate 2 |
| GSM587073 |
AR52Q A574D, vehicle-treated, replicate 3 |
| GSM587074 |
AR52Q A574D, vehicle-treated, replicate 4 |
| GSM587075 |
AR52Q A574D, DHT-treated, replicate 1 |
| GSM587076 |
AR52Q A574D, DHT-treated, replicate 2 |
| GSM587077 |
AR52Q A574D, DHT-treated, replicate 3 |
| GSM587078 |
AR52Q, vehicle-treated, replicate 1, expt 2 |
| GSM587079 |
AR52Q, vehicle-treated, replicate 2, expt 2 |
| GSM587080 |
AR52Q, vehicle-treated, replicate 3, expt 2 |
| GSM587081 |
AR52Q, vehicle-treated, replicate 4, expt 2 |
| GSM587082 |
AR52Q, DHT-treated, replicate 1, expt 2 |
| GSM587083 |
AR52Q, DHT-treated, replicate 2, expt 2 |
| GSM587084 |
AR52Q, DHT-treated, replicate 3, expt 2 |
| GSM587085 |
AR52Q, DHT-treated, replicate 4, expt 2 |
| GSM587086 |
AR52Q + limpet duplication, vehicle-treated, replicate 1, expt 2 |
| GSM587087 |
AR52Q + limpet duplication, vehicle-treated, replicate 2, expt 2 |
| GSM587088 |
AR52Q + limpet duplication, vehicle-treated, replicate 3, expt 2 |
| GSM587089 |
AR52Q + limpet duplication, vehicle-treated, replicate 4, expt 2 |
| GSM587090 |
AR52Q + limpet duplication, DHT-treated, replicate 1, expt 2 |
| GSM587091 |
AR52Q + limpet duplication, DHT-treated, replicate 2, expt 2 |
| GSM587092 |
AR52Q + limpet duplication, DHT-treated, replicate 3, expt 2 |
| GSM587093 |
AR52Q + limpet duplication, DHT-treated, replicate 4, expt 2 |
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| Relations |
| BioProject |
PRJNA130695 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE23802_RAW.tar |
115.4 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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