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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
Statement of
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.
RMID: 0020130776
DOI: 10.1093/hmg/ddt130
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Appears in Collections:Molecular and Biomedical Science publications

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