PhD defence: Cellular Waste Management - The Presence and Removal of Protein Aggregates in the Nucleus and Cytosol

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The cells in our bodies contain many different proteins that are essential for cellular survival. These proteins function by repairing DNA damage, regulating cell division and balancing production and removal of important metabolites. However, mutations and ageing can cause proteins to unfold and lose their functionality. Moreover, these unfolded proteins can cluster together into toxic aggregates that are associated with many neurodegenerative diseases.

In this doctoral thesis, we study how cells prevent this toxicity by removing protein aggregates, and investigate the toxicity associated with protein aggregates that are not efficiently removed. In the first chapters (2 and 3), we introduce a novel tool for inducing protein aggregates, enabling precise monitoring of aggregate clearance in living cells. We use this tool to study aggrephagy, a cellular process that targets entire aggregates for degradation. In chapter 3 we adapt our tool to study how cells remove protein aggregates that are present in the cell nucleus. We find that nuclear aggregates are cleared via alternative mechanism that involves efficient disaggregation and subsequent nuclear export.

In the last part of this thesis, we study the toxicity of protein aggregates associated with Huntington’s disease, where mutated huntingtin protein accumulates in neurons and forms intranuclear aggregates. Using a cellular system, we monitor the integrity of nuclei containing protein aggregates and reveal that huntingtin aggregates can cause nuclear rupture. Such ruptures result in the mixing of cellular compartments, which could contribute to many aspects of neurodegenerative disease.

Together, our work introduces novel tools to study aggregate removal in cells, and provides insight into the toxicity disease related protein aggregates.

Start date and time
End date and time
Location
Hybride: online (livestream link) and for invited guests in the Utrecht University Hall, Domplein 29
PhD candidate
G. Korsten
Dissertation
Cellular Waste Management - The Presence and Removal of Protein Aggregates in the Nucleus and Cytosol
PhD supervisor(s)
prof. dr. L.C. Kapitein
dr. H.D. Mac Gillavry
More information
Full text via Utrecht University Repository