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Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
2005 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, Vol. 1731, no 3, 149-153 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the cerebellum, brainstem and retina. The disease is caused by a polyglutamine expansion in ataxin-7, a protein with largely unknown function. To improve our knowledge of the expression and function of wild-type and expanded ataxin-7, we looked for alternative SCA7 transcripts in mice. We identified a murine SCA7 isoform (SCA7b) containing an uncharacterized exon homologous to the newly identified human exon 12b. Northern blot analysis revealed three exon 12b containing transcripts with molecular sizes of 7.5, 4.4 and 3.0 kb in mice. This contrasted with the situation in humans, where only one exon 12b-containing transcript was observed. Furthermore, Northern blot of the human 4.4 kb SCA7b isoform predominantly showed expression in the brain, while expression of both the murine 7.5-kb and the 4.4-kb transcripts were observed in several tissues including brain, heart, liver, kidney and testis. Quantitative real-time RT-PCR analysis revealed that in muscle and heart SCA7b is the predominant SCA7 isoform, while in brain equal levels of SCA7a and SCA7b was observed. Insertion of exon 12b into the murine SCA7 ORF resulted in a frame-shift that gave rise to an alternative ataxin-7 protein (ataxin-7b). The novel 58-amino acid C-terminus in ataxin-7b directed the protein to a more cytoplasmic location.

Place, publisher, year, edition, pages
2005. Vol. 1731, no 3, 149-153 p.
Keyword [en]
polyglutamine, ataxin-7, CAG repeat, alternative splicing, amino acid sequence, animals, base sequence, brain/enzymology/metabolism, cloning, molecular, cytoplasm/metabolism, exons, frameshift mutation, humans, mice, molecular sequence data, nerve tissue proteins/chemistry/*genetics/metabolism, open reading frames, protein isoforms/*genetics/metabolism, sequence homology, amino acid, species specificity
National Category
Medical Genetics
URN: urn:nbn:se:umu:diva-3801DOI: doi:10.1016/j.bbaexp.2005.10.004PubMedID: 16297465OAI: diva2:142676
Artikeln har vid publiceringen delvis fått en annan titel än den hade vid publiceringen av avhandlingen.Available from: 2004-03-17 Created: 2004-03-17 Last updated: 2010-08-24Bibliographically approved
In thesis
1. Expression and functional analysis of the SCA7 disease protein ataxin-7
Open this publication in new window or tab >>Expression and functional analysis of the SCA7 disease protein ataxin-7
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av uttrycket och funktionen av SCA7 sjukdomsproteinet ataxin-7
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease characterized by cerebellar ataxia and visual problems due to a progressive and selective loss of neurons within the cerebellum, brainstem and retina. The disease is caused by the expansion of a CAG repeat in the first coding exon of the SCA7 gene, resulting in an expanded polyglutamine domain in the N-terminal part of ataxin-7, a protein of unknown function.

To expand our knowledge of the ataxin-7 protein and the mechanism by which mutant ataxin-7 causes disease, we have studied the expression and function of both the normal and the mutated ataxin-7 protein.

Ataxin-7 expression was examination in brain and non-CNS tissues from SCA7 patients and age-matched controls. Expression was predominantly nuclear in neurons throughout the brain of both healthy and SCA7 individuals. We also observed aggregation of mutant ataxin-7 in the nuclei of neurons. No obvious difference in the expression level of ataxin-7 or the formation of aggregates could be observed between affected and non-affected brain regions in SCA7 patients. Based on these findings, we could conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression levels or to the formation of ataxin-7 aggregates.

To widen our studies on ataxin-7 expression, we isolated and characterized the mouse SCA7 gene homolog. Cloning of the mouse SCA7 gene revealed two SCA7 mRNA isoforms that were highly homologous to their human counterparts. Immunohistochemical analysis also revealed a conserved expression pattern of ataxin-7 in adult mouse brain. In addition, ataxin-7 expression was observed during embryonic development in brain as well as in several non-neuronal tissues such as heart, liver and lung.

Besides SCA7, eight neurodegenerative disorders are known to be caused by expanded polyglutamine repeats, including SCA 1-3, 6 and 17, DRPLA, SBMA and Huntington’s disease. The polyglutamine disorders have many features in common and a common pathological disease mechanism involving transcriptional dysregulation has been proposed. To investigate the possible involvement of transcriptional dysregulation in SCA7 pathology, we analyzed the effects of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP, the Purkinje cell-expressed nuclear receptor RORα1 or a basic TATA promoter. As previously shown for other polyglutamine disease proteins, expansion of the polyglutamine domain in ataxin-7 leads to reduced transcription. Surprisingly, strong repression of CBP-mediated, RORα1-mediated and basal transcription was also observed with wild-type ataxin-7, suggesting that the normal ataxin-7 protein may have a role in transcriptional regulation.

129 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 886
Molecular biology, Polyglutamine disease, CAG repeat, Spinocerebellar ataxia type 7, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
urn:nbn:se:umu:diva-214 (URN)91-7305-628-6 (ISBN)
Public defence
2004-04-16, Hörsal Betula, 6M, Umeå Universitet, Umeå, 09:00
Available from: 2004-03-17 Created: 2004-03-17Bibliographically approved

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