Hijacking PrP(c)-dependent signal transduction: when prions impair Aβ clearance

Abstract

The cellular prion protein PrP(c) is the normal counterpart of the scrapie prion protein PrP (Sc), the main component of the infectious agent of transmissible spongiform encephalopathies. The recent discovery that PrP (c) can serve as a receptor for the amyloid beta (Aβ) peptide and relay its neurotoxicity is sparking renewed interest on this protein and its involvement in signal transduction processes. Disease-associated PrP (Sc) shares with Aβ the ability to hijack PrP (c)-dependent signaling cascades, and thereby instigate pathogenic events. Among these is an impairment of Aβ clearance, uncovered in prion-infected neuronal cells. These findings add another facet to the intricate interplay between PrP (c) and Aβ. Here, we summarize the connection between PrP-mediated signaling and Aβ clearance and discuss its pathological implications.

Keywords: Alzheimer’s disease; Aβ clearance; cellular prion protein; prion infection; signal transduction.

FIGURE 1

Schematic representation of the secondary structure of PrP^c. The alpha-cleavage (green) occurs at position 111/112 and generates the N1 and C1 fragments. The beta-cleavage (orange) occurs in the vicinity of octapeptide repeats (ORs), which bind copper ions, and generates the N2 and C2 fragments. PrP^c can also be shed from the plasma membrane through the action of ADAM10. The protective factor STI-1 binds to PrP^c at amino acids 113–128. Two main binding sites have been mapped for Aβ to the very N-terminus (AA 23–50) and near the alpha-cleavage site at amino acids 92–110. The alpha helices (α) and beta sheets (β) are shown in purple and the polybasic regions (+) are shown in red.

FIGURE 2

Schematic representation of the corruption of PrP^c-mediated signaling in prion-infected cells. PrP^Sc accumulation is associated with the constitutive recruitment of various effectors of PrP^c, including the Fyn kinase, the MAP kinases ERK1/2 and the CREB transcription factor. Prion-infected cells also exhibit recruitment of the stress-associated kinases p38 and JNK, which mirrors oxidative stress conditions. A downstream event in this cascade is the drastic reduction in MMP-9 mRNAs and activity, which, in turn, causes an impairment in Aβ clearance, leading to Aβ accumulation. Aβ oligomers would bind PrP^c and possibly PrP^Sc and further fuel the activation of this signaling cascade, thereby sustaining a vicious circle.