Prion diseases are associated with the conformational conversion of cellular
prion protein (PrP(C)) to pathological β-sheet
isoforms (PrP(Sc)), which is the infectious agent beyond comprehension. Increasing evidence indicated that an unknown toxic gain of function of PrP(sc) underlies neuronal death. Conversely, strong evidence indicated that cellular
prion protein might be directly cytotoxic by mediating neurotoxic signaling of β-sheet-rich conformers independent of
prion replication. Furthermore, the common properties of β-sheet-rich
isoform such as PrP(Sc) and β
amyloid protein become the lynchpin that interprets the general pathological mechanism of
protein misfolding diseases. Dysfunction of the
ubiquitin-
proteasome system (UPS) has been implicated in various
protein misfolding diseases. However, the mechanisms of this impairment remain unknown in many cases. In
prion disease,
prion-infected mouse brains have increased levels of
ubiquitin conjugates, which correlate with decreased
proteasome function. Both PrP(C) and PrP(Sc) accumulate in cells after
proteasome inhibition, which leads to increased cell death. A direct interaction between 20S core particle and PrP
isoforms was demonstrated. Here we review the ability of misfolded PrP and UPS to affect each other, which might contribute to the pathological features of
prion-mediated neurodegeneration.