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https://hdl.handle.net/2440/79921
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Type: | Journal article |
Title: | Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases |
Author: | Samaraweera, S. O'Keefe, L. Price, G. Venter, D. Richards, R. |
Citation: | Human Molecular Genetics, 2013; 22(14):2811-2819 |
Publisher: | Oxford Univ Press |
Issue Date: | 2013 |
ISSN: | 0964-6906 1460-2083 |
Statement of Responsibility: | Saumya E. Samaraweera, Louise V. O’Keefe, Gareth R. Price, Deon J. Venter, and Robert I. Richards |
Abstract: | Dominantly inherited expanded repeat neurodegenerative diseases are caused by the expansion of variable copy number tandem repeat sequences in otherwise unrelated genes. Some repeats encode polyglutamine that is thought to be toxic; however, other repeats do not encode polyglutamine indicating either multiple pathogenic pathways or an alternative common toxic agent. As these diseases share numerous clinical features and expanded repeat RNA is a common intermediary, RNA-based pathogenesis has been proposed, based on its toxicity in animal models. In Drosophila, double-stranded (rCAG.rCUG(∼100)) RNA toxicity is Dicer dependent and generates single-stranded (rCAG)7, an entity also detected in affected Huntington's Disease (HD) brains. We demonstrate that Drosophila rCAG.rCUG(∼100) RNA toxicity perturbs several pathways including innate immunity, consistent with the observation in HD that immune activation precedes neuronal toxicity. Our results show that Drosophila rCAG.rCUG(∼100) RNA toxicity is dependent upon Toll signaling and sensitive to autophagy, further implicating innate immune activation. In exhibiting molecular and cellular hallmarks of HD, double-stranded RNA-mediated activation of innate immunity is, therefore, a candidate pathway for this group of human genetic diseases. |
Keywords: | Neurons Animals Humans Huntington Disease Disease Models, Animal Drosophila Proteins RNA, Double-Stranded Signal Transduction Trinucleotide Repeat Expansion Autophagy Female Male Toll-Like Receptors |
Rights: | © The Author 2013. |
DOI: | 10.1093/hmg/ddt130 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/453674 http://purl.org/au-research/grants/nhmrc/627183 |
Published version: | http://dx.doi.org/10.1093/hmg/ddt130 |
Appears in Collections: | Aurora harvest 4 Molecular and Biomedical Science publications |
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