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.
Highlights
Familial prion disorders of humans segregate with mutations in the prion protein gene (PRNP)
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
The 21-kDa fragment has been observed in Creutzfeldt-Jakob disease, the 8-kDa fragment appears specific to Gerstmann-Straussler-Scheinker disease (GSS) (6 – 8)
Summary
Familial prion disorders of humans segregate with mutations in the prion protein gene (PRNP). We show that the metabolism of PrP102L is altered, resulting in accumulation of a 20-kDa fragment of PrP on the cell surface, with a concomitant decrease in the expression of 18-kDa fragment, a product of normal recycling of PrP from the plasma membrane [15].
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