Aggregation-promoting factors in neurodegenerative diseases: Insights from a C. elegans model

Olga Alvarenga Fernandes Sin

    Research output: ThesisThesis fully internal (DIV)

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    One of the hallmarks of neurodegenerative diseases – including Alzheimer’s, Parkinson’s and polyglutamine diseases – is the presence of protein aggregates in the brains of affected patients. One major hurdle in the field is that we do not know why protein aggregation occurs and how it correlates to pathogenesis.
    In this thesis, we took advantage of a C. elegans model for polyglutamine aggregation to find genes that promoted protein aggregation and toxicity. This led to the discovery of the novel genetic modifier of aggregation moag-2 (modifier of aggregation-2), a gene that when mutated suppresses protein aggregation up to 51%. Whole-genome sequencing revealed the causative gene of moag-2 to be lir-3. We found that moag-2/lir-3 is a transcriptional regulator of small non-coding RNAs, which are essential for the regulation of gene expression or the modification of other RNA molecules. Once we had determined the function of MOAG-2/LIR-3, we were surprised to learn that MOAG-2/LIR-3 promotes polyglutamine aggregation in a manner that is independent of its function. In fact, we argue that polyglutamine recruits MOAG-2/LIR-3 to promote aggregation and propose a scenario where aggregation-prone proteins can trigger a toxic switch of function in cellular proteins and hijack them to promote aggregation. Another unprecedented finding from this work is that the presence of polyglutamine induces the downregulation of snRNA, snoRNA and tRNA genes in wild type animals. Although we do not yet know the biological consequences of this observation, it suggests that aggregation-prone proteins can also affect the homeostasis of non-coding RNA.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    • Nollen, Ellen, Supervisor
    • Relvas Bettencourt, J., Co-supervisor, External person
    • Guryev, Victor, Co-supervisor
    Award date13-Jan-2016
    Place of Publication[Groningen]
    Print ISBNs978-90-367-8534-1
    Electronic ISBNs978-90-367-8533-4
    Publication statusPublished - 2016

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