Caenorhabditis elegans models for protein misfolding diseases

Many neurodegenerative diseases are associated with the formation of protein inclusions in the brain. Most of these inclusions contain disease-specific misfolded proteins such as α-synuclein in Parkinson’s disease, and polyglutamine
(polyQ)-protein in polyQ diseases, such as Huntington’s disease. Finding and elucidating the molecular pathways involved in toxic protein aggregation related to disease will help us to understand these diseases. In this thesis, we take advantage
of a thorough understanding of the biology, aging and genetics of a small animal model, C. elegans, the nematode roundworm. C. elegans is transparent, allowing fluorescent microscopy to be used to study protein misfolding and aggregation in vivo. First, we established and validated a model based on the conjugation of yellow fluorescent protein (YFP) to study α-synuclein misfolding and fibril formation in vitro and we created a C. elegans model to track accumulation of α-synuclein in vivo. Second, we used genetic screening in an existing polyQ disease model and in our model for α-synuclein inclusion formation to find novel modifiers of inclusion formation. The conserved modulator of polyQ aggregation, moag-4, found by forward mutagenesis, appears to act by driving intermediate polyQ species into inclusions. Interestingly, loss-of-function of this gene increases lifespan in C. elegans. The genes we found to alter α-synuclein inclusion formation by genome-wide RNAi, including aging genes, are different from the genes previously found to modify polyQ aggregation, suggesting there are different mechanisms underlying these two disease-related processes. The genes we found in these screens represent starting points for further dissection of the molecular pathways and are candidate genes for potential treatments to reduce disease or may influence the risk of developing these diseases.

	Titel en inhoudsopgave
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	Algemene discussie
	Engelse samenvatting
	Samenvatting
	Samenvatting voor de leek
	Dankwoord
	Curriculum vitae
	Bibliopraphie
	Volledige dissertatie

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