The cellular
prion protein, PrPC , is a
copper-binding protein abundantly expressed in the brain, particularly by neurons, and its conformational conversion into the amyloidogenic
isoform, PrPSc , plays a key pathogenic role in
prion diseases. However, the role of
copper binding to PrPC in
prion diseases remains unclear. Here, we fed mice with a low-
copper or regular diet and intracerebrally inoculated them with two different mouse-adapted RML
scrapie and BSE
prions. Mice with a low-
copper diet developed disease significantly but only slightly later than those with a regular diet after inoculation with BSE
prions, but not with RML
prions, suggesting that
copper could play a minor role in BSE
prion pathogenesis, but not in RML
prion pathogenesis. We then generated two lines of transgenic mice expressing mouse PrP with
copper-binding
histidine (His) residues in the N-terminal domain replaced with
alanine residues, termed TgPrP(5H > A)-7342/Prnp0/0 and TgPrP(5H > A)-7524/Prnp0/0 mice, and similarly inoculated RML and BSE
prions into them. Due to 2-fold higher expression of PrP(5H > A) than PrPC in wild-type (WT) mice, TgPrP(5H > A)-7524/Prnp0/0 mice were highly susceptible to these
prions, compared to WT mice. However, TgPrP(5H > A)-7342/Prnp0/0 mice, which express PrP(5H > A) 1.2-fold as high as PrPC in WT mice, succumbed to disease slightly, but not significantly, later than WT mice after inoculation with RML
prions, but significantly so after inoculation with BSE
prions. Subsequent secondary inoculation experiments revealed that amino acid sequence differences between PrP(5H > A) and WT PrPSc created no
prion transmission barrier to BSE
prions. These results suggest that
copper-binding His residues in PrPC are dispensable for RML
prion pathogenesis but have a minor effect on BSE
prion pathogenesis. Taken together, our current results suggest that
copper could have a minor effect on
prion pathogenesis in a strain-dependent manner through binding to His residues in the N-terminal domain of PrPC .