NR AIKK
AU Mishra,R.S.; Gu,Y.; Bose,S.; Verghese,S.; Kalepu,S.; Singh,N.
TI Cell surface accumulation of a truncated transmembrane prion protein in Gerstmann-Sträussler-Scheinker disease P102L
QU The Journal of Biological Chemistry 2002 Jul 5; 277(27): 24554-61
PT journal article
AB 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 (PrPsc) 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, PrPsc 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 PrPsc 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 PrPsc infection by providing an optimal substrate, or by amplifying the neurotoxic signal of PrPsc. Thus, altered susceptibility of PrP(101L) mice to exogenous PrPsc may be mediated by the 20-kDa (Ctm)PrP fragment, rather than PrP(102L) per se.
MH Amino Acid Substitution; Animal; Brain/metabolism; Cell Membrane/*metabolism; Genetic Predisposition to Disease; Gerstmann-Sträussler-Scheinker Disease; Human; Mice; Mice, Transgenic; Neuroblastoma; PrPsc Proteins/*genetics/metabolism; Recombinant Proteins/metabolism; Sequence Deletion; Support, U.S. Gov't, P.H.S.; Transfection; Tumor Cells, Cultured
AD Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
SP englisch
PO USA