Group leader: Ronald Melki
Starting from January 1st, 2015, our team will be part of Neuro-PSI (Neuroscience Paris-Saclay Institute).
The accumulation of protein aggregates within the central nervous system is the hallmark of several progressive neurodegenerative disorders (e.g. Alzheimer, Parkinson, Huntington and Creutzfeldt-Jacob diseases). These aberrant protein conformers are the consequence of the misfolding and aggregation of specific proteins. We demonstrated recently that the protein aggregates that are tightly associated to pathology spread from cell to cell in a prion-like manner reminiscent of PrP in Creutzfeld-Jacob disease.
The goals of our research are to :
i- Decipher the molecular events leading to the aggregation of polypeptides that propagate from one cell to another and amplify by recruiting the soluble form of their constituting polypeptides, ii- document the role of the players that maintain protein homeostasis within the cells, as the protein aggregates we are interested in form upon impairment of this cellular process, iii- characterize the “functional” properties of the different high-molecular weight oligomeric species that form during assembly, and iv- identify the routes used by these protein assemblies to spread from one cell to another, using a combination of cell biological, biochemical and biophysical methods.
Methods and expertise:
Protein expression (in bacteria and yeast) and purification ; cell culture; site directed mutagenesis and protein labeling ; thermodynamic and kinetic (including rapid, stopped-flow) methods of protein-protein interaction and self-assembly ; Spectroscopy (UV, visible, IR, circular dichroism) ; spectrofluorimetry and light scattering ; proteomic methods (limited proteolysis, cross-linking, mass spectrometry) ; mapping of surface interfaces involved in protein-protein interactions (H/D exchange and mass spectrometry) ; protein crystallography and structural analysis ; confocal and electron microscopy