The role of normal cellular
prion protein (PrP) remains to be fully elucidated; however, the
protein is crucial for the
infection and progression of
prion diseases. Recent evidence indicates that PrP is a
metalloprotein since the octapeptide repeat sequences in the
protein have high affinity for various
divalent cations and the binding sites appear to play a role in the pathogenesis of
prion diseases. In our present study, we tested several divalent metals including
manganese and
cadmium and determined their effects on protein degradation and
protein aggregation in mouse neuronal cells expressing PrP.
Cadmium was more neurotoxic than
manganese following 24h exposure.
Manganese did not show any significant effect on the inhibition of proteasomal activity or formation of high molecular weight ubiquitinated PrPs. Interestingly, treatment with
cadmium profoundly inhibited proteasomal activity, which resulted in greatly increased formation of high molecular weight ubiquitinated PrPs. Immunohistochemical analysis also revealed a dramatic increase in formation of oligomers after
cadmium treatment.
Cadmium also increased the formation of ubiquitinated PrP, but it did not lead to the formation of
proteinase-K resistant PrP. Collectively, our results show that a divalent
metal,
cadmium affects proteasomal function and PrP aggregation, which promote neurotoxicity.