Triplet repeat-derived siRNAs enhance RNA-mediated toxicity in a Drosophila model for myotonic dystrophy

• Published in: PLoS genetics 2011-03, Vol.7 (3), p.e1001340
• Main Authors: Yu, Zhenming, Teng, Xiuyin, Bonini, Nancy M
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila; Drosophila - genetics; Drosophila - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Drosophila Proteins - toxicity; Female; Gene Expression Regulation - physiology; Genetic aspects; Genetic transcription; Kinases; Male; Mutation - genetics; Myotonic dystrophy; Myotonic Dystrophy - genetics; Myotonic Dystrophy - metabolism; Neurological Disorders/Neuromuscular Diseases; Physiological aspects; Proteins; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Ribonucleic acid; Risk factors; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Toxicity; Transcription, Genetic - genetics; Trinucleotide Repeat Expansion - genetics; Trinucleotide Repeats - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1001340

More than 20 human neurological and neurodegenerative diseases are caused by simple DNA repeat expansions; among these, non-coding CTG repeat expansions are the basis of myotonic dystrophy (DM1). Recent work, however, has also revealed that many human genes have anti-sense transcripts, raising the possibility that human trinucleotide expansion diseases may be comprised of pathogenic activities due both to a sense expanded-repeat transcript and to an anti-sense expanded-repeat transcript. We established a Drosophila model for DM1 and tested the role of interactions between expanded CTG transcripts and expanded CAG repeat transcripts. These studies revealed dramatically enhanced toxicity in flies co-expressing CTG with CAG expanded repeats. Expression of the two transcripts led to novel pathogenesis with the generation of dcr-2 and ago2-dependent 21-nt triplet repeat-derived siRNAs. These small RNAs targeted the expression of CAG-containing genes, such as Ataxin-2 and TATA binding protein (TBP), which bear long CAG repeats in both fly and man. These findings indicate that the generation of triplet repeat-derived siRNAs may dramatically enhance toxicity in human repeat expansion diseases in which anti-sense transcription occurs.