Correct protein folding is essential for the functioning of living cells and organisms. Many human diseases are associated with protein misfolding and aggregation, which lead to toxicity and cell death by largely unknown mechanisms. The Sinnige lab is a new team within the section Membrane Biochemistry & Biophysics at the Bijvoet Centre for Biomolecular Research, and is currently seeking two highly motivated and enthusiastic PhD candidates to investigate the molecular mechanisms of protein aggregation in vivo using C. elegans as a model organism.
Project 1 explores the fundamental biophysical properties of aggregation-prone proteins within a living organism. You will make use of C. elegans expressing fluorescently labelled polyglutamine, which is related to Huntington’s disease, and track the kinetics of protein aggregation by microscopy as the animal is ageing. Quantitative analysis of the aggregation kinetics in different genetic backgrounds will allow you to address key questions in the field regarding the mechanisms of protein aggregation in a living animal. For example, why are some cell types more vulnerable to protein aggregation than others? What causes molecular chaperones to fail in preventing protein aggregation?
Project 2 addresses the mechanisms of protein aggregation in relation to biological membranes. A variety of disease-associated peptides and proteins are known to interact with cellular membranes, which play an important yet poorly understood role in the aggregation mechanism. You will use existing transgenic C. elegans models, and create novel ones to uncover the features of membrane-associated protein aggregation using fluorescence microscopy and biochemical methods. The use of C. elegans furthermore allows you to observe the behaviour of the animals (e.g. movement, response to chemicals) to assess the toxicity caused by protein aggregation. You will also use these approaches to test small molecules that have the potential to interfere with protein-membrane interactions and the aggregation process, thereby reducing the toxic effects.