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    Investigating the Role of Mutant Huntingtin mRNA in Huntington’s Disease

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    Authors
    Ly, Socheata
    Faculty Advisor
    Anastasia Khvorova
    Academic Program
    Translational Science
    UMass Chan Affiliations
    RNA Therapeutics Institute
    Document Type
    Doctoral Dissertation
    Publication Date
    2020-10-28
    Keywords
    Huntington's disease
    repeat-associated neurodegenerative diseases
    antisense oligonucleotides
    ASOs
    RNA foci
    RNA clusters
    RNA aggregates
    Cell Biology
    Molecular and Cellular Neuroscience
    Molecular Biology
    
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    Abstract
    Mutant mRNA and protein both contribute to the clinical manifestation of many repeat-associated neurodegenerative and neuromuscular disorders. The presence of nuclear RNA clusters is a feature shared amongst these diseases, such as C9ORF72/ALS and myotonic dystrophy 1/2 (DM1/2); however, this pathological hallmark has not been conclusively demonstrated in Huntington’s disease (HD) in vivo. Investigations into HD – caused by a CAG repeat expansion in exon 1 of the huntingtin (HTT) gene – have largely focused on toxic protein gain-of-function as a disease-causing feature, with fewer studies investigating the role of mutant HTT mRNA in pathology or pathogenesis. Here we report that in two HD mouse models, YAC128 and BACHD-97Q-ΔN17, mutant HTT mRNA is preferentially retained in the nucleus in vivo. Furthermore, we observed the early, widespread formation of large mutant HTT mRNA clusters (approximately 0.6 to 5 µm3 in size) present in over 50-75% of striatal and cortical neurons. Affected cells were limited to one cluster at most. Endogenous wild-type mouse Htt or human HTT mRNA containing 31 or fewer repeats did not form clusters. Additionally, the aberrantly spliced N-terminal exon 1-intron 1 RNA fragment, HTT1a, also formed clusters that fully co-localized with the mutant HTT mRNA clusters. These results suggest that multiple repeat-containing transcripts can coalesce to form a single cluster in a given cell. Treating YAC128 mice with antisense oligonucleotides efficiently silenced individual HTT mRNA foci but had limited impact on clusters. Our findings identify mutant HTT mRNA clustering as an early, robust molecular signature of HD, further supporting HD as a repeat expansion disease with suspected mRNA involvement.
    DOI
    10.13028/x0ym-8h64
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31345
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/x0ym-8h64
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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