Conformational diseases

Many diseases, particularly those affecting seniors, result from abnormalities in the structure and conformation of proteins. These effects may be profound, such as structural changes observed in neurodegenerative diseases (such as Creutzfeld-Jakob disease and Alzheimer’s disease), or may involve more subtle modifications, such as where mutated proteins are not correctly localized within the cell. These diseases impose a huge burden on society. In Quebec, we estimate that among those who are over 65 years old, 70,000 will develop Alzheimer’s disease, and 25,000 Parkinson’s disease. In Quebec alone, cystic fibrosis (CF) affects 1 newborn in every 3,600, and in the Saguenay-Lac Saint-Jean region, 1 in every 15 people carries the gene responsible for the disease.

The teams of John Hanrahan and David Thomas have developed a research program to identify molecular chaperones capable of correcting the trafficking default of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) responsible for the disease. The efforts made by talented young scientists combined with important research grants from the Canadian and American Cystic Fibrosis Foundations has led to the identification of promising compounds. These molecules correct the trafficking defect of CFTR and increase its activity in the control of cellular ionic flux. These compounds are from different chemical classes which suggest several mechanisms. One of the next challenges is to determine the structure of these active compounds with their protein targets.

Gergely Lukacs’ research group studies the trafficking of CFTR and other aspects of the molecular and cellular biology of CF. With the acquisition of a mass spectrometer, Gergely Lukacs will be a key player of the core facilities.

NMR is an excellent tool to characterize the interactions between molecules. It is used for both fragment-based screening or SAR-by-NMR, and to identify the interaction site on the protein. It can also predict if a compound will affect the protein folding. Kalle Gehring’s research team led NMR studies on CFTR, showing the importance of ATP in the protein stability.

Some forms of Parkinson’s disease are the result of genetic mutations which cause the unfolding of the proteins produced by the mutated gene. Kalle Gehring’s research team collaborates with Edward Fon (Montreal Neurological Insitute) to determine the three-dimensional structure of the ubiquitin-like domain of the Parkin protein which plays a key role in the degradation of proteins in neurons. A malfunction of Parkin could lead to the accumulation of potentially toxic proteins in dopaminergic neurons. The use of NMR to help design small molecules favoring the folding of this mutated protein could lead to the development of new inhibitors of neurodegeneration.

The long QT syndrome (LQST), leading to arrhythmia or cardiac arrest, is due to the blockage induced by therapeutics, of the human ether-a-go-go-related-gene (hERG) potassium channels located in cell membranes of myocardium. Isabelle Marcotte’s research group uses NMR to determine the binding sites of cardio-toxic therapeutics on hERG channels, along with the structural modifications of these channel induced by such therapeutics. Jason Young’s research team studies the role of chaperones in hERG channel synthesis.