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Expression and functional analysis of the SCA7 disease protein ataxin-7
Umeå University, Faculty of Medicine, Molecular Biology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Studier av uttrycket och funktionen av SCA7 sjukdomsproteinet ataxin-7 (Swedish)
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.

Place, publisher, year, edition, pages
2004. , 129 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 886
Keyword [en]
Molecular biology, Polyglutamine disease, CAG repeat, Spinocerebellar ataxia type 7
Keyword [sv]
Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-214ISBN: 91-7305-628-6 (print)OAI: oai:DiVA.org:umu-214DiVA: diva2:142678
Public defence
2004-04-16, Hörsal Betula, 6M, Umeå Universitet, Umeå, 09:00
Opponent
Supervisors
Available from: 2004-03-17 Created: 2004-03-17Bibliographically approved
List of papers
1. Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals
Open this publication in new window or tab >>Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals
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2002 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 1, 29-37 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

Keyword
spinocerebellar ataxia type 7, ataxin-7, expression, subcellular localization
Identifiers
urn:nbn:se:umu:diva-3799 (URN)10.1007/s00401-001-0514-4 (DOI)
Available from: 2004-03-17 Created: 2004-03-17 Last updated: 2017-12-14Bibliographically approved
2. Cloning and expression analysis of the murine homolg of the Spinocerebellar ataxia type 7 (SCA7) gene
Open this publication in new window or tab >>Cloning and expression analysis of the murine homolg of the Spinocerebellar ataxia type 7 (SCA7) gene
Show others...
2002 In: Gene, Vol. 285, no 1-2, 91-99 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3800 (URN)
Available from: 2004-03-17 Created: 2004-03-17Bibliographically approved
3. Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice
Open this publication in new window or tab >>Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice
2005 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, 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.

Keyword
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
Identifiers
urn:nbn:se:umu:diva-3801 (URN)doi:10.1016/j.bbaexp.2005.10.004 (DOI)16297465 (PubMedID)
Note
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: 2018-01-13Bibliographically approved
4. A role for both wild-type and expanded ataxin-7 in transcriptional regulation
Open this publication in new window or tab >>A role for both wild-type and expanded ataxin-7 in transcriptional regulation
2005 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 20, no 3, 646-655 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.

Keyword
spinocerebellar ataxia type 7, polyglutamine, CAG repeat, acetylation, CREB-binding protein/genetics, cell nucleus/genetics/metabolism, cerebellum/*metabolism/pathology/physiopathology, child, histones/metabolism, humans, male, mutation/genetics, nerve tissue proteins/*genetics, promoter regions (genetics)/genetics, purkinje cells/metabolism/pathology, receptor protein-tyrosine kinases, receptors; cell surface/genetics, regulatory elements; transcriptional/*genetics, repressor proteins/genetics, silencer elements, transcriptional/genetics, spinocerebellar ataxias/*genetics/metabolism/physiopathology, trans-activation (genetics)/genetics, trinucleotide repeat expansion/genetics, tumor cells, cultured
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-3802 (URN)10.1016/j.nbd.2005.04.018 (DOI)15936949 (PubMedID)
Available from: 2004-03-17 Created: 2004-03-17 Last updated: 2018-01-13Bibliographically approved

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