Research Interest

Damaged and misfolded proteins that cannot be repaired have to be eliminated in the cell. Failure to do so leads to the accumulation of these proteins that will then aggregate. Protein aggregation is a hallmark of a large number of neurodegenerative pathologies including Parkinson’s and Prion diseases. The ubiquitin proteasome system pays a major role in targeting aberrant proteins for proteolysis. In this system, target proteins are first modified by the covalent attachment of ubiquitin and then recognized and degraded by the proteasome. Equally important is that cancer cells also rely on the ubiquitin proteasome system and there are currently three proteasome inhibitors approved by the FDA to treat certain types of tumours representing a multi-billions USD market. Using a combination of cell biology, biochemical and proteomic approaches, our lab is interested in understanding how the cell recognizes misfolded proteins to target them for ubiquitylation and proteolysis.

There is a variety of projects available such as:

- Characterization of the role of ubiquitination in the heat stress response;

- Identification of novel quality control degradation pathways in mammalian cells;

- Characterize how the proteome is affected upon aging and in stress conditions;

- Develop novel proteomic approaches to probe protein homeostasis;

- Utilize experimental evolution in order to modify protein homeostasis.



The Ubiquitin System

Ubiquitylation is a post-translational modification in which ubiquitin, a 76-amino acid residue protein, is covalently attached to a lysine residue of a protein substrate. The multi-step reaction is driven a E1 activating enzyme, a E2 conjugating enzyme, and a E3 ligase. The ubiquitin system is a vast network of proteins that encompasses more than 500 putative E3 ubiquitin-ligases and as many as 80 DUBs encoded in the human genome. Since each E3 can presumably target several substrates, ubiquitylation is one of the main post-translational modifications and its impact on the proteome is expected to be comparable to phosphorylation. Another hallmark of the ubiquitin system is its implication in several diseases like cancers and neurodegenerative disorders including Parkinson’s disease. Hence, deciphering the network of enzyme-target interactions in the ubiquitin system is of great importance. For a better explanation watch our video on ubiquitin.


Protein Aggregation in Disease

Protein aggregation is a hallmark of a large number of pathologies. These aggregates are thought to arise from the inability of the cell to degrade insoluble, misfolded and damaged proteins. Misfolded proteins normally bind to molecular chaperones of the heat-shock protein family, which shield hydrophobic domains from the cytosol and assist folding. Aggregation may be induced by the extended exposure of misfolded domains and non-specific hydrophobic interactions that result in the formation of amorphous structures. Alternatively, aggregation can be induced by highly ordered β–strand fibrils that form insoluble amyloids. A major view is that aggregation may prevent cytotoxicity by shielding other proteins from non-specific interactions. Aggregation also provides a mechanism to cluster non-degraded misfolded proteins in one location where they can then be targeted to the lysosome via macro-autophagy. Thus the inability to sequester misfolded proteins into aggregates (also called aggresomes) may be a key factor in inducing cell death.


Ubiquitin and Protein Aggregation

Impairment of the ubiquitin system has been linked to protein aggregation. A major function of ubiquitination is to target proteins for degradation by the proteasome, a large complex composed of over 30 different proteins. A large fraction of the proteasome substrates consists of misfolded polypeptides and the proteasome is cardinal to cell homeostasis. One prevalent theory is that dysfunction of the proteasome leads to the aggregation of the non-degraded proteins. Indeed, ubiquitin is enriched in most symptomatic aggregates and proteasome inhibition has also been shown to induce the formation of specific protein aggregates, e.g., inclusions enriched with α–synuclein similar to the Lewy bodies of Parkinson’s disease. Better insight into these pathways may lead to a major breakthrough in the understanding of some neurodegenerative diseases.