Anchorless prion protein forms plaques

Abstract

To ascertain the role of prion protein (PrP) in scrapie infection, researchers infected transgenic mice that lacked the cell-membrane anchor for the protein. The anchorless mice were susceptible to scrapie infection but, paradoxically, did not develop clinical symptoms. Furthermore, they showed neuropathological changes—fibrils, plaques, and vacuoles—that resembled Alzheimer’s disease rather than scrapie (Science 2005; 308: 1435–39). Under normal conditions, PrP is tethered to the cell surface by a glycosylphosphatidylinositol (GPI) membrane anchor. Conversion of normal PrP to the disease causing protease-resistant form of PrP may occur at the cell membrane. The researchers assessed the pathogenesis of scrapie infection in transgenic mice expressing PrP lacking the GPI membrane anchor. “We were very interested in whether the tethering of PrP to the membranes of cells where it was produced by this GPI anchor was important to the disease process”, lead author Bruce Chesebro (Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT, USA) told The Lancet Neurology. Chesebro’s team intracerebrally inoculated the anchorless mice and control mice with three different scrapie strains. In control mice, clinical disease was evident by 140 days, whereas no neurological signs were seen in the anchorless mice after 600 days. The researchers confirmed replication of the scrapie agent in the anchorless mice by use of titration experiments with infected brain homogenates. “It is striking that anchoring is not required for the formation of PrP scrapie, contrary to previous belief”, Charles Weissmann (Department of Infectology, Scripps Florida, Jupiter, FL, USA) comments. “Another striking feature is you can accumulate a lot of PrP scrapie without detectable clinical disease. One possibility is that the toxic form of PrP scrapie has to exercise its toxicity inside the cell, so once it doesn’t have an anchor, there is no endocytosis.” Chesebro thinks that the lack of toxicity in the absence of the GPI anchor may be comparable to the issue of plaques versus protofibrils in Alzheimer’s disease. “The plaques still cause damage but not as much as the protofibrils”, he explains. “It may be something similar with PrP. I think that our data hint at this, because we have a lot of plaques, and we don’t have too much damage.” Alternatively, the researchers may have missed the symptoms in the anchorless mice, because they were not easily detected, says Chesebro. The researchers are exploring this possibility by use of more sophisticated neurophysiological testing. “We also think they may develop symptoms if we wait a little bit longer”, he adds.