Frederic Rousseau and Joost Schymkowitz Lab

Research focus

​The VIB Switch Laboratory, K.U.Leuven 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.

First we aim at creating a more accurate picture of the aggregation propensity of the human proteome and the effect of genome variability hereupon. In order to achieve this we created a set of bioinformatics tools (TANGO & WALTZ) that capture the sequence-specific determinants of protein aggregation and performed an analysis on the impact of aggregation on disease-associated mutations (SNPeffect). In doing so we found that aggregation is not restricted to a set of amyloid diseases but that many metabolic diseases and cancer are also affected by aggregation.
Second, we aim at understanding how gain-of-function of protein aggregates is effected in both cancer and neurodegeneration by mapping the aggregation-specific interactome in these different contexts.
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.

Publications

Selectivity of aggregation-determining interactionsGanesan A, Debulpaep M, Wilkinson H, Van Durme J, De Baets G, Jonckheere W, Ramakers M, Ivarsson Y, Zimmermann P, Van Eldere J, Schymkowitz J, Rousseau FJOURNAL OF MOLECULAR BIOLOGY, e-pub, e-pub, 2014
Gain of function of mutant p53 by coaggregation with multiple tumor suppressorsXu J, Reumers J, Couceiro J, De Smet F, Gallardo R, Rudyak S, Cornelis A, Rozenski J, Zwolinska A, Marine J, Lambrechts D, Suh Y, Rousseau F, Schymkowitz JNature Chemical Biology, 7, 285-95, 2011
Exploring the sequence determinants of amyloid structure using position-specific scoring matricesMaurer-Stroh S, Debulpaep M, Kuemmerer N, De La Paz M, Martins I, Reumers J, Morris K, Copland A, Serpell L, Serrano L, Schymkowitz J, Rousseau FNATURE METHODS, 7, 237-42, 2010
Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta(42) to Abeta(40) ratioKuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D'hooge R, Martins I, Rousseau F, Schymkowitz J, De Strooper BEMBO JOURNAL, 29, 3408-20, 2010
Protein sequences encode safeguards against aggregationReumers J, Maurer-Stroh S, Schymkowitz J, Rousseau FHUMAN MUTATION, 30, 431-7, 2009

News

Cancer turns out to be a p53 protein aggregation disease

28/03/2011 - Protein aggregation, generally associated with Alzheimer’s and mad cow disease, turns out to play a significant role in cancer. Certain mutations of p53 cause the protein to aggregate, disrupting its protective function.

Are lipids in the brain an important factor for Alzheimer's disease, Flemish scientists crack the code

10/12/2007 - VIB researchers have now discovered that certain lipids, present also in our brains, promote the formation of this protofibril.

TANGO − towards faster prognosis of Alzheimer’s and Parkinson’s diseases

10/09/2004 - VIB researchers have developed TANGO − a statistical method that can predict the susceptibility of proteins to sticking together.TANGO enables the prediction of risky protein alterations that underlie various diseases.

Frederic Rousseau

Frederic Rousseau

Research area(s)

Bio

PhD student: University of Cambridge, UK, 1998
PhD: EMBL, Heidelberg, Germany, 2001
Assistent Prof: Vrije Universiteit Brussel, Belgium, 2004
Prof: KU Leuven, Belgium, 2011
VIB Group Leaders since September 2003

Contact Info

VIB Switch LaboratoryKU LeuvenO&N 1Campus GasthuisbergHerestraat 49 box 802 rm 08.683 3000 LEUVENRoute description
Joost Schymkowitz

Joost Schymkowitz

Research area(s)

Bio

PhD student: University of Cambridge, UK, 1998
PhD: EMBL, Heidelberg, Germany, 2001
Prof: Vrije Universiteit Brussel, Belgium, 2004
VIB Group Leaders since September 2003

Contact Info

VIB Switch LaboratoryKU LeuvenO&N 1Campus GasthuisbergHerestraat 49 box 802 rm 08.683 3000 LEUVENRoute description