Grant: Project Grant

Misfolding of proteins resulting from genetic mutations is a frequent cause of inherited diseases known as conformational diseases. Since G protein-coupled receptors (GPCRs) are involved in most physiological functions, mutations of members of this large protein family are associated with many such diseases. In most cases, disease-causing GPCR mutations lead to inappropriate folding of the receptors and their intracellular retention by the quality control system of the cells. Given that, to mediate their actions, GPCRs must be targeted to the cell surface, their intracellular retention results in a loss of function that cause the diseases. In recent years, we and others have identified compounds, named pharmacological chaperones (PCs), capable of rescuing folding, cell surface targeting and function of these mutated receptors, opening a path for developing treatments for conformational diseases. However, the mechanisms by which PC rescue misfolded GPCRs remain poorly understood, limiting our ability to design therapeutically effective PCs. In fact, the therapeutic potential of PCs has only been assessed in a handful of relevant preclinical models. The present project therefore aims at uncovering the mechanisms underlying PC action. For this purpose, severe early onset obesity (SEOO) resulting from mutations in the melanocortin type-4 receptor will be used as a prototypical model. In combination with computer-assisted drug discovery approaches, the basic knowledge gained on the processes controlling GPCR intracellular retention by the quality control system of the cell and the mechanisms underlying PC action will be used to identify effective PCs. These potential therapeutic candidates will then be tested in a genetic mouse model of SEOO generated in our laboratory. In addition to open the path for the development of potential treatments for SEOO, the information gained will be relevant for other inherited conformational diseases resulting from GPCR mutations.