Our research is focused on understanding the mechanisms gearing protein folding and misfolding and their relation to human disease. In particular we are investigating how protein aggregation affects the interactome by suppressing native interactions but also by introducing novel aggregation-specific interactions. The latter are especially relevant as they are are usually associated to gain of function activities such as neurotoxicity (neurodegeneration) or cell proliferation (cancer).
The significance of protein misfolding and aggregation on the development of human disease is often underestimated and its consequences poorly understood. Indeed, so far only a few dozen aggregation-associated diseases have been identified, mostly neurodegenerative disorders or systemic amyloidoses. However, protein folding is often an inefficient process that has to be tightly controlled by the protein quality control machinery of the cell. Moreover the risk of protein misfolding and aggregation increases with age due to gradual waning of the cell’s capacity to direct protein folding and degradation. Why then are so few aggregation-associated diseases identified?
Neurodegenerative diseases are associated with a cytotoxic gain-of-function phenotype facilitating the incrimination of protein aggregates. However, many aggregating proteins may lack such cytotoxic gain-of-function or display gain-of-function phenotypes, which are currently not associated to protein aggregation. Indeed, we showed that although protein aggregation can lead to cytotoxic gain-of-function in neurodegeneration, on the contrary in cancer protein aggregation contributes to cell proliferation and immortalization. How can protein aggregation lead to such diverse gain-of-function activities?
Are these differences due to cell-specific or function-specific contexts or does the ability of aggregates from different proteins to interact with cellular chaperones dictate their physiological effect?
Our goal therefore is twofold.
Our experimental approach to tackle these questions is based on an interdisciplinary approach combining bioinformatics, biophysical analysis of protein aggregates but also molecular and cellular biological studies of aggregation in human cell culture and model organisms including zebrafish and mice.