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  • 1
    Online Resource
    Online Resource
    Impaired Motor Learning in Mice Expressing TorsinA with the DYT1 Dystonia Mutation
    Society for Neuroscience ; 2005
    In:  The Journal of Neuroscience Vol. 25, No. 22 ( 2005-06-01), p. 5351-5355
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 25, No. 22 ( 2005-06-01), p. 5351-5355
    Abstract: Primary early-onset generalized dystonia is an autosomal dominant disorder caused by a deletion (ΔGAG) in the DYT1 gene encoding torsinA. The gene defect has incomplete penetrance, with ∼30% of carriers developing clinically evident dystonia. We describe lines of transgenic mice that express either human mutant torsinA (hMT) or human wild-type (hWT) torsinA. All mice demonstrated moderately increased levels of torsinA in the brain by Western blot analysis and normal subcellular distribution of torsinA in neurons by confocal microscopy. No animals had dystonic features. However, mice overexpressing hMT, but not hWT, torsinA displayed a reduced ability to learn motor skills in an accelerating rotarod paradigm. This pattern resembles the impaired motor sequence learning demonstrated in human nonmanifesting carriers of the ΔGAG mutation. Open-field testing showed no differences in spontaneous activity between transgenic mice and their nontransgenic littermates, indicating that mice overexpressing hMT torsinA did not develop overtly abnormal motor behavior. Together, these data suggest that these transgenic mice provide a useful model of the ΔGAG carrier state that can be used to probe genetic and environmental factors that can trigger the dystonic state.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0855-05.2005
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2005
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 51 ( 2017-12-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 51 ( 2017-12-19)
    Abstract: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1 . This unique insertion coincides with six additional noncoding sequence changes in TAF1 , the gene that encodes TATA-binding protein–associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients ( n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT) n . The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1712526114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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