Publication
Aggregation-promoting factors in neurodegenerative diseases: Insights from a C. elegans model
Alvarenga Fernandes Sin, O., 2016, [Groningen]: University of Groningen. 179 p.Research output: Thesis › Thesis fully internal (DIV)

Documents
- Title and contents
Final publisher's version, 640 KB, PDF document
- Chapter 1
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- Chapter 2
Final publisher's version, 2.17 MB, PDF document
- Chapter 3
Final publisher's version, 1.94 MB, PDF document
- Chapter 4
Final publisher's version, 4.91 MB, PDF document
- Chapter 5
Final publisher's version, 1.68 MB, PDF document
- Chapter 6
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- Chapter 7
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- Summary
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- Samenvatting
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- Resumo
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- Acknowledgements
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- List of publications
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- Complete thesis
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- Propositions
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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 language | English |
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Qualification | Doctor of Philosophy |
Awarding Institution | |
Supervisors/Advisors |
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Award date | 13-Jan-2016 |
Place of Publication | [Groningen] |
Publisher | |
Print ISBNs | 978-90-367-8534-1 |
Electronic ISBNs | 978-90-367-8533-4 |
Publication status | Published - 2016 |
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