Please use this identifier to cite or link to this item:
|Scopus||Web of Science®||Altmetric|
|Title:||Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases|
van Eyk, C.
|Citation:||Human Molecular Genetics, 2011; 20(19):3757-3768|
|Publisher:||Oxford Univ Press|
|Kynan T. Lawlor, Louise V. O’Keefe, Saumya E. Samaraweera, Clare L. van Eyk, Catherine J. McLeod, Christopher A. Maloney, Thurston H.Y. Dang, Catherine M. Suter and Robert I. Richards|
|Abstract:||The pathogenic agent responsible for the expanded repeat diseases, a group of neurodegenerative diseases that includes Huntington's disease is not yet fully understood. Expanded polyglutamine (polyQ) is thought to be the toxic agent in certain cases, however, not all expanded repeat disease genes can encode a polyQ sequence. Since a repeat-containing RNA intermediary is common to all of these diseases, hairpin-forming single-stranded RNA has been investigated as a potential common pathogenic agent. More recently, it has become apparent that most of the expanded repeat disease loci have transcription occurring from both strands, raising the possibility that the complementary repeat RNAs could form a double-stranded structure. In our investigation using Drosophila models of these diseases, we identified a fortuitous integration event that models bidirectional repeat RNA transcription with the resultant flies exhibiting inducible pathology. We therefore established further lines of Drosophila expressing independent complementary repeat RNAs and found that these are toxic. The Dicer pathway is essential for this toxicity and in neuronal cells accounts for metabolism of the high copy number (CAG.CUG)100 double-stranded RNAs down to (CAG)7 single-stranded small RNAs. We also observe significant changes to the microRNA profile in neurons. These data identify a novel pathway through which double-stranded repeat RNA is toxic and capable of eliciting symptoms common to neurodegenerative human diseases resulting from dominantly inherited expanded repeats.|
|Keywords:||Neurons; Animals; Animals, Genetically Modified; Humans; Drosophila; Neurodegenerative Diseases; Disease Models, Animal; Ribonuclease III; RNA Helicases; Drosophila Proteins; RNA, Double-Stranded; Trinucleotide Repeat Expansion; Nucleic Acid Conformation; Female; Male|
|Rights:||© The Author 2011. Published by Oxford University Press. All rights reserved.|
|Appears in Collections:||Genetics publications|
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.