ROLE OF INTRACELLULAR TRAFFICKING IN THE PATHOGENESIS OF INHERITED PRION DISEASES

Prion diseases are incurable neurodegenerative disorders that can be both inherited or infectious.The genetic forms, CJD,GSS,FFI, occurr in middle to late adult life and are charachterised by dementia and progressive loss of all body functions due to brain degeneration (death follows after months or years). Prion diseases have received an enormous amount of publicity in Europe and recently in the US due to MAD COW DISEASE (BSE) and its possible spread to humans following ingestion of contaminated material. These diseases can be included in the lager family of amyloidogenic neurological disorders, eg,Alzheimer disease, all of which are fatal and are characterised by spongiform degeneration of the brain and of deposition of amyloid plaques. For all these diseases the primary cause of neurodegeneration is not yet known, but we believe that a common mechanism might be involved. Genetic Prion diseases are linked to germlines mutations in a gene on chromosone 20 (Prnp) which encodes the PrPc protein, an endogenous cellular protein of yet unknown function which undergoes to a pathological conversion to an isoform called PrPSc (prion). PrPSc is believed to catalyse its own replication by converting the endogenous protein into the pathological conformation in a self propagating reaction. The cellular basis of this conversion is not known. From our preliminary data and from data present in the literature, we postulate that alterations in the intracellular trafficking od PrPc have an important role in the pathological conversion as well as in the functional impairment of the protein which may lead to neurodegeneration. Therefore we propose to analyse the metabolism and the intracellular transport of different PrP mutants and compare them with the normal endogenous protein in neuronal cultures. We believe that this study will help understanding the pathogenesis of prion and other neurodegenerative diseases and will provide novel therapeutical and diagnostical approaches.