Defining the role of the cellular prion protein at the intersection of several neurodegenerative diseases

Several age-related disorders are associated with protein misfolding and aggregation in the brain, including Alzheimer's and Parkinson's diseases. Alzheimer's disease is characterized by progressive dementia and accumulation of the amyloid-β (Aβ) peptide, a cleavage product of an endogenous protein (the amyloid precursor protein). Small aggregates of Aβ (called Aβ oligomers) are thought to be primarily responsible for neuronal abnormalities and memory deficits occurring in Alzheimer's disease. The cellular prion protein (abbreviated PrPC), a factor of unknown function expressed at the neuronal surface, has been shown to bind Aβ oligomers and other pathological aggregates, mediating their toxic effects on neuronal cells. Interestingly, PrPC is involved in another kind of neurodegenerative disorders, called prion diseases, which can occur sporadically, be infectious, or genetically inherited. Thus, understanding the role of PrPC on the neuronal surface, and how this protein could mediate neurotoxicity in different pathologies, may provide important insights to understand the pathogenic processes of prion and Alzheimer's diseases, and possibly other neurodegenerative disorders. The purpose of this project is to develop a novel pharmacological approach to investigate the function of PrPC in different physiological and pathological conditions. In addition, we aim at evaluating the therapeutic potentials of a PrPC-directed strategy in experimental models of genetic prion and Alzheimer’s diseases. Our research could provide a completely new pharmacological perspective to treat neurodegenerative disorders.