Blog
About

39
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      RNA Gain-of-Function in Spinocerebellar Ataxia Type 8

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8) CTG CAG expansion produces CUG expansion RNAs (CUG exp) from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAG exp transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1) CUG exp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUG exp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 ( GAT4/Gabt4). In vivo optical imaging studies in SCA8 mice confirm that Gabt4 upregulation is associated with the predicted loss of GABAergic inhibition within the granular cell layer. These data demonstrate that CUG exp transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUG exp disorders. Moreover, our demonstration that relatively short CUG exp transcripts cause RNA gain-of-function effects and the growing number of antisense transcripts recently reported in mammalian genomes suggest unrecognized toxic RNAs contribute to the pathophysiology of polyglutamine CAG CTG disorders.

          Author Summary

          We describe several lines of evidence that RNA gain-of-function effects play a significant role in spinocerebellar ataxia type 8 (SCA8) and has broader implications for understanding the CNS effects of other trinucleotide expansion disorders including myotonic dystrophy type 1, Huntington disease like-2, and spinocerebellar ataxia type 7. The SCA8 mutation is bidirectionally transcribed resulting in the expression of CUG exp transcripts from ATXN8OS and CAG exp transcripts and polyglutamine protein from the overlapping ATXN8 gene. These data suggest that SCA8 pathogenesis involves toxic gain-of-function effects at the RNA (CUG exp) and/or protein (PolyQ) levels. We present three lines of evidence that CUG exp transcripts play a significant role in SCA8: 1) CUG exp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUG exp transcripts trigger alternative splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 ( GAT4/Gabt4) which is associated with the predicted loss of GABAergic inhibition within the granular cell layer in SCA8 mice. Additionally, alternative splicing changes and GAT4 upregulation are induced by CUG exp but not CAG exp transcripts. From a therapeutic viewpoint, it is promising that this change is reversed in cells overexpressing MBNL1.

          Related collections

          Most cited references 46

          • Record: found
          • Abstract: found
          • Article: not found

          Antisense transcription in the mammalian transcriptome.

          Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring "genes" in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            CLIP identifies Nova-regulated RNA networks in the brain.

            Nova proteins are neuron-specific antigens targeted in paraneoplastic opsoclonus myoclonus ataxia (POMA), an autoimmune neurologic disease characterized by abnormal motor inhibition. Nova proteins regulate neuronal pre-messenger RNA splicing by directly binding to RNA. To identify Nova RNA targets, we developed a method to purify protein-RNA complexes from mouse brain with the use of ultraviolet cross-linking and immunoprecipitation (CLIP).Thirty-four transcripts were identified multiple times by Nova CLIP.Three-quarters of these encode proteins that function at the neuronal synapse, and one-third are involved in neuronal inhibition.Splicing targets confirmed in Nova-/- mice include c-Jun N-terminal kinase 2, neogenin, and gephyrin; the latter encodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, two previously identified Nova splicing targets.Thus, CLIP reveals that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in POMA.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

              Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2009
                August 2009
                14 August 2009
                : 5
                : 8
                Affiliations
                [1 ]Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of America
                [2 ]Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota, United States of America
                [3 ]Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
                [4 ]Genetics Institute, University of Florida, Gainesville, Florida, United States of America
                [5 ]Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States of America
                The Hospital for Sick Children and University of Toronto, Canada
                Author notes

                Conceived and designed the experiments: RSD DLT WG YI TJE MSS LPWR. Performed the experiments: RSD DLT WG YI. Analyzed the data: RSD DLT WG YI TJE MSS LPWR. Contributed reagents/materials/analysis tools: MLM TJE MSS LPWR. Wrote the paper: RSD TJE MSS LPWR.

                Article
                09-PLGE-RA-0576R2
                10.1371/journal.pgen.1000600
                2719092
                19680539
                Daughters 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.
                Counts
                Pages: 13
                Categories
                Research Article
                Genetics and Genomics/Disease Models
                Genetics and Genomics/Gene Function
                Genetics and Genomics/Genetics of Disease
                Neurological Disorders
                Neurological Disorders/Movement Disorders
                Neurological Disorders/Neurogenetics
                Neurological Disorders/Neuroimaging
                Neuroscience/Behavioral Neuroscience
                Neuroscience/Motor Systems
                Neuroscience/Neuronal and Glial Cell Biology

                Genetics

                Comments

                Comment on this article