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.
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http://dx.doi.org/10.1093/hmg/ddt130 | DOI Listing |
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January 2025
Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
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View Article and Find Full Text PDFCell Rep
January 2025
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan; Department of Applied Chemistry, National Chiayi University, Chiayi City 600, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 115, Taiwan. Electronic address:
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View Article and Find Full Text PDFBrain Commun
January 2025
Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaR3E 0T6.
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View Article and Find Full Text PDFJ Integr Bioinform
January 2025
Research Center for Molecular Biotechnology and Bioinformatics, Universitas Padjadjaran, Bandung 40133, Indonesia.
The emergence of new variants of SARS-CoV-2, including Alpha, Beta, Gamma, Delta, Omicron variants, and XBB sub-variants, contributes to the number of coronavirus cases worldwide. SARS-CoV-2 is a positive RNA virus with a genome of 29.9 kb that encodes four structural proteins: spike glycoprotein (S), envelope glycoprotein (E), membrane glycoprotein (M), and nucleocapsid glycoprotein (N).
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