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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.

Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases