Cell surface accumulation of a truncated transmembrane prion protein in Gerstmann-Straussler-Scheinker disease P102L.

Abstract	A familial prion disorder with a proline to leucine substitution at residue 102 of the prion protein (PrP(102L)) is typically associated with protease-resistant PrP fragments (PrP(Sc)) in the brain parenchyma that are infectious to recipient animals. When modeled in transgenic mice, a fatal neurodegenerative disease develops, but, unlike the human counterpart, PrP(Sc) is lacking and transmission to recipient animals is questionable. Alternate mice expressing a single copy of PrP(102L) (mouse PrP(101L)) do not develop spontaneous disease, but show dramatic susceptibility to PrP(Sc) isolates from different species. To understand these discrepant results, we studied the biogenesis of human PrP(102L) in a cell model. Here, we report that cells expressing PrP(102L) show decreased expression of the normal 18-kDa fragment on the plasma membrane. Instead, a 20-kDa fragment, probably derived from transmembrane PrP ((Ctm)PrP), accumulates on the cell surface. Because the 20-kDa fragment includes an amyloidogenic region of PrP that is disrupted in the 18-kDa form, increased surface expression of 20-kDa fragment may enhance the susceptibility of these cells to PrP(Sc) infection by providing an optimal substrate, or by amplifying the neurotoxic signal of PrP(Sc). Thus, altered susceptibility of PrP(101L) mice to exogenous PrP(Sc) may be mediated by the 20-kDa (Ctm)PrP fragment, rather than PrP(102L) per se.
Authors	Ravi Shankar Mishra, Yaping Gu, Sharmila Bose, Susamma Verghese, Sudheera Kalepu, Neena Singh
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 27 Pg. 24554-61 (Jul 05 2002) ISSN: 0021-9258 [Print] United States
PMID	11967261 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	PrPSc Proteins Recombinant Proteins
Topics	Amino Acid Substitution Animals Brain (metabolism) Cell Membrane (metabolism) Genetic Predisposition to Disease Gerstmann-Straussler-Scheinker Disease Humans Mice Mice, Transgenic Neuroblastoma PrPSc Proteins (genetics, metabolism) Recombinant Proteins (metabolism) Sequence Deletion Transfection Tumor Cells, Cultured

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