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  • 1
    Online Resource
    Online Resource
    Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation
    IOS Press ; 2021
    In:  Journal of Huntington's Disease Vol. 10, No. 1 ( 2021-02-09), p. 53-74
    Details
    In: Journal of Huntington's Disease, IOS Press, Vol. 10, No. 1 ( 2021-02-09), p. 53-74
    Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large ( 〉 50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.
    Type of Medium: Online Resource
    ISSN: 1879-6397 , 1879-6400
    URL: Article
    DOI: 10.3233/JHD-200433
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2021
    detail.hit.zdb_id: 2673033-9
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  • 2
    Online Resource
    Online Resource
    Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease
    IOS Press ; 2021
    In:  Journal of Huntington's Disease Vol. 10, No. 1 ( 2021-02-09), p. 149-163
    Details
    In: Journal of Huntington's Disease, IOS Press, Vol. 10, No. 1 ( 2021-02-09), p. 149-163
    Abstract: Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.
    Type of Medium: Online Resource
    ISSN: 1879-6397 , 1879-6400
    URL: Article
    DOI: 10.3233/JHD-200423
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2021
    detail.hit.zdb_id: 2673033-9
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  • 3
    Online Resource
    Online Resource
    Age-Dependent Increase in Tau Phosphorylation at Serine 396 in Huntington’s Disease Prefrontal Cortex
    IOS Press ; 2023
    In:  Journal of Huntington's Disease Vol. 12, No. 3 ( 2023-10-03), p. 267-281
    Details
    In: Journal of Huntington's Disease, IOS Press, Vol. 12, No. 3 ( 2023-10-03), p. 267-281
    Abstract: Background: To date, it is still controversial whether tau phosphorylation plays a role in Huntington’s disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. Objective: The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods: Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results: Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusions: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.
    Type of Medium: Online Resource
    ISSN: 1879-6397 , 1879-6400
    URL: Article
    DOI: 10.3233/JHD-230588
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2023
    detail.hit.zdb_id: 2673033-9
    Location Call Number Limitation Availability
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    Online Resource
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