The objective is to test a """"""""membrane"""""""" hypothesis of nerve cell degeneration in prion diseases caused by accumulation of abnormally folded wild-type PrPSc and in those caused by PrP mutations that result in abnormal transmembrane topography of PrP, designated tmPrP. Prion diseases caused by PrPSc accumulation include scrapies and bovine spongiform encephalopathy in animals and sporadic, iatrogenic, and familial Creutzfeldt-Jakob disease and fatal familial insomnia in humans. Prion diseases that might by caused by tmPrP appear to be limited to six dominantly inherited human prion diseases with abundant PrP amyloid formation classified Gerstmann-Straussler-Scheinker syndrome. Our laboratory was the first to show that the conversion of PrPC to nascent PrPSc and the accumulation of the latter in the brain are the cause of nerve cell dysfunction and degeneration in scrapie. More recently, we obtained cell physiological evidence that PrPSc accumulates in the plasma membrane of scrapie-infected cell lines and that this is associated with marked changes in plasma membrane properties and receptor-mediated signal transduction. This led us to a membrane hypothesis which proposes that nerve cell dysfunction and degeneration and prion disease are caused by accumulation of PrPSc or tmPrP in the neurilemma. Here we propose to test this hypothesis in animal models of two categories of prion disease: Those acquired by inoculation with scrapie prions an those caused by mutations of the PrP gene in which transmembrane topography of mutated-PrP features. We propose three Aims. In brief, we will compare the amount of PrPSc or tmPrP that accumulates the in caveolae-like domains (CLDs(, total plasma membrane, and synaptosomal membranes (Aim#2) with the degree of neuropathological changes (vacuolar degeneration, reactive astrocytic gliosis, and nerve cell death) (Aim#1) and with the degree of change in pertinent functions of neuronal membranes (Aim#3) (transmitter release from synaptosomes, second messenger responses and NGF receptor function). The membrane hypothesis will be supported if a correlation can be found between the concentration of PrPSc or tmPrP in the plasma membrane and the degree of neuropathological and functional change.
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