Copper Chelation Delays the Onset of Prion Disease

• Published in: The Journal of biological chemistry Vol. 278; no. 47; pp. 46199 - 46202
• Main Authors: Sigurdsson, Einar M., Brown, David R., Alim, Muhammad A., Scholtzova, Henrieta, Carp, Richard, Meeker, Harry C., Prelli, Frances, Frangione, Blas, Wisniewski, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.11.2003; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Brain Chemistry - drug effects; Chelating Agents - pharmacology; Chelating Agents - therapeutic use; Chelation Therapy - methods; Copper - analysis; Copper - blood; Copper - metabolism; D-penicillamine; Dose-Response Relationship, Drug; Endopeptidase K - drug effects; Endopeptidase K - metabolism; Mice; Mice, Inbred Strains; penicillamine; Penicillamine - pharmacology; Penicillamine - therapeutic use; Prion Diseases - drug therapy; Prion Diseases - prevention & control; PrPSc Proteins - chemistry; PrPSc Proteins - drug effects; PrPSc Proteins - metabolism; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C300303200

The prion protein (PrP) binds copper and under some conditions copper can facilitate its folding into a more protease resistant form. Hence, copper levels may influence the infectivity of the scrapie form of prion protein (PrPSc). To determine the feasibility of copper-targeted therapy for prion disease, we treated mice with a copper chelator, d-(–)-penicillamine (d-PEN), starting immediately following intraperitoneal scrapie inoculation. d-PEN delayed the onset of prion disease in the mice by about 11 days (p = 0.002), and reduced copper levels in brain by 29% (p < 0.01) and in blood by 22% (p = 0.03) compared with control animals. Levels of other metals were not significantly altered in the blood or brain. Modest correlation was observed between incubation period and levels of copper in brain (p = 0.08) or blood (p = 0.04), indicating that copper levels are only one of many factors that influence the rate of progression of prion disease. In vitro, copper dose-dependently enhanced the proteinase K resistance of the prion protein, and this effect was counteracted in a dose-dependent manner by co-incubation with d-PEN. Overall, these findings indicate that copper levels can influence the conformational state of PrP, thereby enhancing its infectivity, and this effect can be attenuated by chelatorbased therapy.