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      A Pathogenic Mechanism in Huntington's Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity

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          Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.

          Author Summary

          Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal CAG expansion in the Huntingtin gene ( HTT), resulting in an expanded polyglutamine track in the HTT protein. Longer CAG expansions correlate with an earlier more severe manifestation of the disease that produces choreic movement, behavioural and psychiatric disturbances, and dementia. Although the causative gene is widely expressed, neuropathology is characterized by striatal and cortical atrophy. HTT interacts with proteins involved in transcription, cell signaling, and transport. The pathogenic role of mutant HTT is not fully understood. This study shows that CAG expanded HTT RNA also contributes to neuronal toxicity. Mutant HTT RNA gives rise to small CAG-repeated RNAs (sCAGs) with neurotoxic activity. These short RNAs interfere with cell functions by silencing the expression of genes that are fully or partially complementary, through a mechanism similar to that of microRNAs. These findings suggest that a small RNA–dependent mechanism may contribute to HD neuronal cell loss. The exhaustive identification of the target genes modulated by sCAGs may lead to a better understanding of HD pathology, allowing the development of new therapeutic strategies.

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          Most cited references 54

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              Argonaute2 is the catalytic engine of mammalian RNAi.

              Gene silencing through RNA interference (RNAi) is carried out by RISC, the RNA-induced silencing complex. RISC contains two signature components, small interfering RNAs (siRNAs) and Argonaute family proteins. Here, we show that the multiple Argonaute proteins present in mammals are both biologically and biochemically distinct, with a single mammalian family member, Argonaute2, being responsible for messenger RNA cleavage activity. This protein is essential for mouse development, and cells lacking Argonaute2 are unable to mount an experimental response to siRNAs. Mutations within a cryptic ribonuclease H domain within Argonaute2, as identified by comparison with the structure of an archeal Argonaute protein, inactivate RISC. Thus, our evidence supports a model in which Argonaute contributes "Slicer" activity to RISC, providing the catalytic engine for RNAi.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                February 2012
                February 2012
                23 February 2012
                : 8
                : 2
                [1 ]Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
                [2 ]Network of Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
                [3 ]Institute of Neuropathology, IDIBELL-Bellvitge University Hospital, L'Hospitalet de Llobregat, Catalonia, Spain
                [4 ]Network of Biomedical Research in Neurodegenerative Disorders (CIBERNED), Madrid, Spain
                [5 ]Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain
                The Hospital for Sick Children and University of Toronto, Canada
                Author notes

                Conceived and designed the experiments: M Bañez-Coronel, E Martí. Performed the experiments: M Bañez-Coronel, S Porta, B Kagerbauer, E Mateu-Huertas, L Pantano. Analyzed the data: M Bañez-Coronel, E Martí. Wrote the paper: M Bañez-Coronel, X Estivill, E Martí. Generated the Flag-Ago2 stable cell lines: S Porta. Provided and characterised neuro-pathological samples of HD and control subjects: I Ferrer. Provided brain samples of HD murine model: M Guzmán. Conceived and directed the research: X Estivill, E Martí.

                Bañez-Coronel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Research Article
                Molecular Cell Biology
                Gene Expression
                Nucleic Acids



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