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 (PrP102L) 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 PrP102L (mouse PrP101L) 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 PrP102L in a cell model. Here, we report that cells expressing PrP102L show decreased expression of the normal 18-kDa fragment on the plasma membrane. Instead, a 20-kDa fragment, probably derived from transmembrane PrP (CtmPrP), 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 PrP101L mice to exogenous PrPSc may be mediated by the 20-kDa ctmPrP fragment, rather than PrP102L per se.