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Vol. 12, Issue 4, 881-889, April 2001
Department of Cell Biology and Physiology, Washington University
School of Medicine, St. Louis, Missouri 63110
Although there is considerable evidence that PrPSc is
the infectious form of the prion protein, it has recently been proposed that a transmembrane variant called CtmPrP is the direct
cause of prion-associated neurodegeneration. We report here, using a
mutant form of PrP that is synthesized exclusively with the
CtmPrP topology, that CtmPrP is retained in the
endoplasmic reticulum and is degraded by the proteasome. We also
demonstrate that CtmPrP contains an uncleaved, N-terminal
signal peptide as well as a C-terminal glycolipid anchor. These results
provide insight into general mechanisms that control the topology of
membrane proteins during their synthesis in the endoplasmic reticulum, and they also suggest possible cellular pathways by which
CtmPrP may cause disease.
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