Prion disease: exponential growth requires membrane binding.
A hallmark feature of prions, whether in mammals or yeast and fungi, is exponential growth associated with fission or autocatalysis of protein aggregates. We have employed a rigorous kinetic analysis to recent data from transgenic mice lacking a glycosylphosphatidylinositol membrane anchor to the normal cellular PrP(C) protein, which show that toxicity requires the membrane binding. We find as well that the membrane is necessary for exponential growth of prion aggregates; without it, the kinetics is simply the quadratic-in-time growth characteristic of linear elongation as observed frequently in in vitro amyloid growth experiments with other proteins. This requires both: i), a substantial intercellular concentration of anchorless PrP(C), and ii), a concentration of small scrapies seeding aggregates from the inoculum, which remains relatively constant with time and exceeds the concentration of large polymeric aggregates. We also can explain via this analysis why mice heterozygous for the anchor-full/anchor-free PrP(C) proteins have more rapid incubation than mice heterozygous for anchor-full/null PrP(C), and contrast the mammalian membrane associated fission or autocatalysis with the membrane free fission of yeast and fungal prions.
Department of Physics, University of California-Davis, Davis, CA 95616, USA.
Daniel L
DL
Cox
Rajiv R P
RR
Sing
Sichun
S
Yang
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000235:genetics; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism*; D011485:Protein Binding
D017261:Glycosylphosphatidylinositols; D018621:PrPC Proteins; D018620:PrPSc Proteins