Deregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease

Judith Schilling, Meike Broemer, Ilian Atanassov, Yvonne Duernberger, Ina Vorberg, Christoph Dieterich, Alina Dagane, Gunnar Dittmar, Erich Wanker, Willeke van Roon-Mom, Jennifer Winter, Sybille Krauß*

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    46 Citations (Scopus)


    Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin (HTT) gene, translating into an elongated polyglutamine stretch. In addition to the neurotoxic mutant HTT protein, the mutant CAG repeat RNA can exert toxic functions by trapping RNA-binding proteins. While few examples of proteins that aberrantly bind to mutant HTT RNA and execute abnormal function in conjunction with the CAG repeat RNA have been described, an unbiased approach to identify the interactome of mutant HTT RNA is missing. Here, we describe the analysis of proteins that preferentially bind mutant HTT RNA using a mass spectrometry approach. We show that (I) the majority of proteins captured by mutant HTT RNA belong to the spliceosome pathway, (II) expression of mutant CAG repeat RNA induces mis-splicing in a HD cell model, (III) overexpression of one of the splice factors trapped by mutant HTT ameliorates the HD phenotype in a fly model and (VI) deregulated splicing occurs in human HD brain. Our data suggest that deregulated splicing is a prominent mechanism of RNA-induced toxicity in HD.

    Original languageEnglish
    Pages (from-to)1869-1877
    Number of pages9
    JournalJournal of Molecular Biology
    Issue number9
    Publication statusPublished - 19 Apr 2019


    • CAG repeat RNA
    • RNA-binding proteins
    • neurodegeneration
    • polyglutamine disease
    • spliceosome


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