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| Status |
Public on Apr 05, 2013 |
| Title |
Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases |
| Organism |
Drosophila melanogaster |
| Experiment type |
Expression profiling by array
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| Summary |
Dominantly inherited expanded repeat neurodegenerative diseases are typically caused by the expansion of existing variable copy number tandem repeat sequences in otherwise unrelated genes. Repeats located in translated regions encode polyglutamine that is thought to be the toxic agent, however in several instances the expanded repeat is in an untranslated region, necessitating multiple pathogenic pathways or an alternative common toxic agent. As numerous clinical features are shared by several of these diseases, and expanded repeat RNA is a common intermediary, RNA has been proposed as a common pathogenic agent. Various forms of repeat RNA are toxic in animal models, by multiple distinct pathways. In Drosophila, repeat-containing double-stranded RNA (rCAG.rCUG~100) toxicity is dependent on Dicer processing evident with the presence of single-stranded rCAG7, which have been detected in affected HD brains. Microarray analysis of Drosophila rCAG.rCUG~100 repeat RNA toxicity revealed perturbation of several pathways including innate immunity. Recent reports of elevated circulating cytokines prior to clinical onset, and age-dependent increased inflammatory signaling and microglia activation in the brain, suggest that immune activation precedes neuronal toxicity. Since the Toll pathway is activated by certain forms of RNA, we assessed the role of this pathway in RNA toxicity. We find that rCAG.rCUG~100 activates Toll signaling and that RNA toxicity is dependent on this pathway. The sensitivity of RNA toxicity to autophagy further implicates innate immune activation. Expression of rCAG.rCUG~100 was therefore directed in glial cells and found to be sufficient to cause neuronal dysfunction. Non-autonomous toxicity due to expanded repeat-containing double-stranded RNA mediated activation of innate immunity is therefore proposed as a candidate pathway for this group of human genetic diseases.
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| Overall design |
The heads from newly eclosed male Drosophila were used for RNA extraction and profiling on Affymetrix Drosophile Genome 2.0 microarrays. Nine samples were analysed, representing control and experimental lines. Two independent lines of rCAG.rCUG~100 double-stranded RNA were analysed in triplicate. These were compared to 4xUAS control analysed in triplicate. All transgenes were expressed using the elavII-GAL4 pan-neuronal driver. Candidates were selected from the pool of transcripts which showed a 'present' call in all samples. T-tests were performed on raw values to determine samples that showed a significant difference with a P-value < 0.05.
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| Contributor(s) |
Samaraweera SE, Price GR, Venter DJ, Richards RI |
| Citation(s) |
23525903 |
| Submission date |
Dec 13, 2012 |
| Last update date |
May 04, 2018 |
| Contact name |
Gareth Price |
| E-mail(s) |
nscalehome@gmail.com
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| Phone |
61413289611
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| Organization name |
Queensland Facility for Advanced Bioinformatics
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| Street address |
Carmody Road
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| City |
Brisbane |
| State/province |
Queensland |
| ZIP/Postal code |
4072 |
| Country |
Australia |
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| Platforms (1) |
| GPL1322 |
[Drosophila_2] Affymetrix Drosophila Genome 2.0 Array |
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| Samples (9)
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| GSM1053259 |
Drosophila heads_elavII>4xUAS, triplicate repeat 1 |
| GSM1053260 |
Drosophila heads_elavII>4xUAS, triplicate repeat 2 |
| GSM1053261 |
Drosophila heads_elavII>4xUAS, triplicate repeat 3 |
| GSM1053262 |
Drosophila heads_elavII>rCAG.rCUG100_independent line S1, triplicate repeat 1 |
| GSM1053263 |
Drosophila heads_elavII>rCAG.rCUG100_independent line S1, triplicate repeat 2 |
| GSM1053264 |
Drosophila heads_elavII>rCAG.rCUG100_independent line S1, triplicate repeat 3 |
| GSM1053265 |
Drosophila heads_elavII>rCAG.rCUG100_independent line S2, triplicate repeat 1 |
| GSM1053266 |
Drosophila heads_elavII>rCAG.rCUG100_independent line S2, triplicate repeat 2 |
| GSM1053267 |
Drosophila heads_elavII>rCAG.rCUG100_independent line S2, triplicate repeat 3 |
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| Relations |
| BioProject |
PRJNA183854 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE42910_RAW.tar |
19.6 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| GSE42910_t-test_and_log-ratio_data.txt.gz |
4.7 Mb |
(ftp)(http) |
TXT |
| Processed data provided as supplementary file |
| Processed data included within Sample table |
| Processed data are available on Series record |
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