ERA-Net E-Rare

Genetic prion diseases, including Gerstmann-Sträussler-Scheinker syndrome fatal familial insomnia and genetic Creutzfeldt-Jakob disease are dominantly inherited neurodegenerative disorders linked to point mutations and insertions in the PRNP gene encoding the cellular prion protein (PrPC). Disease-associated mutations favor PrPC misfolding and aggregation, leading to accumulation of pathogenic, neurotoxic forms of the protein in the brain. Currently there is no cure for genetic prion diseases, and they are invariably fatal. In this project, we propose to block mutant PrP aggregation by stabilizing the native conformation of the monomeric precursors. The underlying concept is to prevent aggregation of mutant PrP by increasing the Gibbs free energy barrier (∆G) required for the initial misfolding events. This goal could be achieved with small ligands of PrP capable of acting as pharmacological chaperones. In order to identify and characterize such compounds, we propose a multidisciplinary approach combining medicinal chemistry, biochemistry, biophysics, cellular biology and efficacy tests in animal models of disease. Our approach will lay the groundwork for the development of completely new classes of drugs for genetic prion diseases.