INVESTIGATION OF THE MOLECULAR DETERMINANTS OF NEUROTOXICITY AND INFECTIVITY OF A MUTANT PRION PROTEIN

Prion diseases, including Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia are fatal neurodegenerative disorders characterized by dementia, motor dysfunction and cerebral amyloidosis. These diseases affect both humans and animals, and can be infectious, sporadic and genetic in origin. Prion diseases have attracted enormous scientific attention because they exemplify a novel mechanism of biological information transfer based on the transmission of protein conformation rather than on the inheritance of nucleic acid sequence. They have also had profound impact on public health because of compelling evidence that bovine spongiform encephalopathy, or “mad cow disease”, has been transmitted to human beings by consumption of contaminated beef. Prions are postulated to arise from the change in the shape of a single normal protein of the brain (prion protein, PrP), to an altered disease-causing form, called PrP scrapie (PrPSc). PrPSc 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 and motor dysfunction. Inherited prion diseases are due to mutations in the PrP gene, which are believed to alter the structure of PrP and induce its conversion to PrPSc. In this research project, we intend to study the biological mechanisms underlying the inherited forms of prion diseases by using transgenic mice. These are animals in which the mutated gene that causes the disease in humans has been introduced by means of genetic engineering. In particular, we plan to investigate how the mutated PrP is transformed into an altered form able to propagate itself and kill neurons. We expect that these investigations will lead to a better understanding of the pathogenesis of prion diseases and will allow us to develop a therapy for these diseases.