Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases
| Autor: | Robert I. Richards, Kynan T. Lawlor, Thurston H. Y. Dang, Catherine J. McLeod, Louise V. O'Keefe, Clare L. van Eyk, Catherine M. Suter, Saumya E. Samaraweera, Christopher A. Maloney |
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| Přispěvatelé: | Lawlor, Kynan T, O'Keefe, Louise V, Samaraweera, Saumya E, van Eyk, Care L, McLeod, Catherine J, Maloney, Christopher A, Dang, Thurston HY, Suter, Catherine M, Richards, Robert I |
| Rok vydání: | 2011 |
| Předmět: |
Male
Ribonuclease III polymerase chain reaction diptera drosophila genes neurodegenerative disorders neurons rna Biology Animals Genetically Modified Transcription (biology) microRNA Genetics Animals Drosophila Proteins Humans Molecular Biology Gene Genetics (clinical) RNA Double-Stranded Neurons double-stranded eye pathology rna toxic effect micro rna polyglutamine RNA Neurodegenerative Diseases General Medicine Disease Models Animal RNA silencing Nucleic Acid Conformation Drosophila Female Dicer Pathway Trinucleotide Repeat Expansion Trinucleotide repeat expansion RNA Helicases Drosophila Protein |
| Zdroj: | Human Molecular Genetics. 20:3757-3768 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddr292 |
| Popis: | 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 singlestranded 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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