CELLULAR MECHANISMS OF SYNAPTIC DYSFUNCTION IN INHERITED PRION DISEASES

Prion diseases, including Creutzfeldt-Jakob disease, Gerstmann-Sträussler Scheinker syndrome, fatal familial insomnia and kuru in humans, mad cow disease (BSE), and scrapie in sheep, are fatal neurodegenerative disorders arising from the conformational conversion of a single normal protein of the brain (prion protein, PrP) to an altered disease-causing form. This altered form of PrP accumulates in the brains of the patients and causes abnormal proliferation of certain cells of the brain (gliosis), holes in the brain tissue (spongiosis), and loss of neurons (neurodegeneration), leading to dementia, motor dysfunction and other neurological symptoms. Prion diseases can be sporadic, infectious or inherited. Inherited prion diseases are due to mutations in the PrP gene, which are believed to alter the structure of PrP and favor its conversion to a disease-causing form. The aim of the present study is to investigate the mechanism by which mutant PrP induces disease and how different PrP mutations cause different diseases in humans. For this purpose, we will use transgenic mice that express the mutant gene and that model essential aspects of the human diseases. In particular, we aim at identifying the mechanisms leading to abnormal function of neurons and alteration of their communication (synaptic dysfunction). We hope that this study will improve our understanding of prion diseases and contribute to establishing the rationale for the development of an effective therapy for these devastating disorders.