NR AWDH
AU Chesebro,B.; Trifilo,M.; Meade-White,K.; Race,R.E.; Masliah,E.; Knowlton,K.; Oldstone,M.
TI Role of PrP membrane anchoring in brain and extraneural pathogenesis of prion diseases
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-21
PT Konferenz-Vortrag
AB Prion protein (PrP) conversion from the normal protease-sensitive form (PrPsen) to the disease-associated protease-resistant form (PrPres) is an important event in the pathogenesis of prion diseases. Normal PrP exists primarily bound to the cellular plasma membrane by a glycosylphosphatidylinositol (GPI) linkage, and conversion to the disease-associated form is believed to occur mainly as a membrane-associated event. Our previous experiments demonstrated that PrP lacking the GPI anchor could be converted to protease-resistant PrP in tissue culture cells and in cellfree in vitro conditions. To test the in vivo influence of GPI anchoring on prion disease infection and disease, we generated and studied transgenic (tg) mice which express only the anchorless GPI-negative PrP. Following scrapie infection of such tg mice we observed replication of scrapie infectivity, accumulation of PrPres in brain mainly as an amyloid form, and vacuolation primarily in white matter areas. Surprisingly there was no typical fatal clinical disease over an observation period of 600-700 days; however, in the later phases minor clinical defects were detectable by neurobiological testing. The lack of fatal prion disease in these tg mice suggests that either the amyloid form of PrPres has a reduced level of neurotoxicity and/or that membrane anchored PrP is required for the usual neurotoxic effects. Further analysis indicated that PrPres could be detected in the heart and blood of infected tg mice, and cardiac studies showed deficits consistent with restrictive cardiomyopathy typical of the early stages of amyloid heart disease in humans.
AD B. Chesebro, K. Meade-White, R. Race: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, Hamilton, Montana, USA; M. Trifilio, M. Oldstone: The Scripps Research Institute, La Jolla, California, USA; E. Masliah, K. Knowlton: University of California at San Diego, La Jolla, California, USA
SP englisch
PO Italien