Copper binding to PrPC may inhibit prion disease propagation.
Although it has been well established that PrP(C), the normal isoform of PrP(Sc), is a copper-binding protein, the role of this metal in the function of PrP(C) as well as in prion disease pathology remains unclear. Here, we show that when scrapie-infected neuroblastoma cells were cultured in the presence of copper, the accumulation of PrP(Sc) in these cells was markedly reduced. In addition, our results indicate that when normal neuroblastoma cells were cultured in the presence of copper ions, they could no longer bind and internalize PrP(Sc). In another set of experiments, copper was added to the drinking water of normal and scrapie-infected hamsters. Our results show that administration of copper to normal hamsters induced cerebellar PrP(C) accumulation. Most important, a significant delay in prion disease onset was observed when scrapie-infected hamsters were treated with copper. As shown before for neuroblastoma cells, also in vivo most of the copper-induced accumulation of PrP(C) was intracellular. We hypothesized that PrP(C) internalization by copper may hinder PrP(Sc) interaction with this molecule, and thereby affect prion disease propagation.
Hijazi
Nuha
N
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Ein Karem, Jerusalem 91120, Israel.
Shaked
Yuval
Y
Rosenmann
Hana
H
Ben-Hur
Tamir
T
Gabizon
Ruth
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D019327:Copper Sulfate / Q000008:administration & dosage / Q000627:therapeutic use*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D007239:Infections; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000517:prevention & control*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011689:Purkinje Cells / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013054:Spectrophotometry, Atomic / Q000379:methods; D013997:Time Factors
D018621:PrPC Proteins; D018620:PrPSc Proteins; D012333:RNA, Messenger; D019327:Copper Sulfate