title: Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases.
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.
authors.affiliation: Discipline of Genetics, School of Molecular & Biomedical Science and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide, Adelaide SA 5005, Australia.
authors.forename: Saumya E
authors.initials: SE
authors.lastname: Samaraweera
authors.forename: Louise V
authors.initials: LV
authors.lastname: O'Keefe
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Price
authors.forename: Deon J
authors.initials: DJ
authors.lastname: Venter
authors.forename: Robert I
authors.initials: RI
authors.lastname: Richards
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: D029721:Drosophila Proteins; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors