FAMILIAL PRION DISEASES: DEVELOPMENT OF EXPERIMENTAL MODELS TO INVESTIGATE PATHOGENIC MECHANISMS AND POTENTIAL THERAPEUTICAL APPROACHES

Prion diseases, including Creutzfeld-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia and kuru in humans, and mad cow disease (BSE) and scrapie in sheep, are fatal neurodegenerative disorders. These are closely related to Alzheimer's disease, with which they share cell biological and neuropathological features. Prion diseases can be sporadic, infectious or genetic and are of enormous scientific interest because they are thought 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 (Tg) mice. Tg mice are animals in which the mutated gene that causes the disease in humans has been introduced by means of genetic engineering. We plan to use Tg mice that model familial prion diseases to investigate how PrPSc causes neurodegeneration and to test potential therapies to prevent the development of the disease. Hopefully, these investigations will lead to a better understanding of the pathogenesis of prion diseases and will allow us to develop a therapy for the human patients. This has recently become urgent, since the outbreak of a new form of prion disease in humans, which arises from the consumption of beef from cattle affected by mad cow disease.