Document Detail

Aberrant metal binding by prion protein in human prion disease.
MedLine Citation:
PMID:  11579148     Owner:  NLM     Status:  MEDLINE    
Human prion diseases are characterized by the conversion of the normal prion protein (PrP(C)) into a pathogenic isomer (PrP(Sc)). Distinct PrP(Sc) conformers are associated with different subtypes of prion diseases. PrP(C) binds copper and has antioxidation activity. Changes in metal-ion occupancy can lead to significant decline of the antioxidation activity and changes in conformation of the protein. We studied the trace element status of brains from patients with sporadic Creutzfeldt-Jakob disease (sCJD). We found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain tissues from sCJD subjects. We have also studied the metal occupancy of PrP in sCJD patients. We observed striking elevation of manganese and, to a lesser extent, of zinc accompanied by significant reduction of copper bound to purified PrP in all sCJD variants, determined by the PrP genotype and PrP(Sc) type, combined. Both zinc and manganese were undetectable in PrP(C) preparations from controls. Copper and manganese changes were pronounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrP(Sc) type-1. Anti-oxidation activity of purified PrP was dramatically reduced by up to 85% in the sCJD variants, and correlated with increased in oxidative stress markers in sCJD brains. These results suggest that altered metal-ion occupancy of PrP plays a pivotal role in the pathogenesis of prion diseases. Since the metal changes differed in each sCJD variants, they may contribute to the diversity of PrP(Sc) and disease phenotype in sCJD. Finally, this study also presented two potential approaches in the diagnosis of CJD; the significant increase in brain manganese makes it potentially detectable by MRI, and the binding of manganese by PrP in sCJD might represent a novel diagnostic marker.
B S Wong; S G Chen; M Colucci; Z Xie; T Pan; T Liu; R Li; P Gambetti; M S Sy; D R Brown
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  78     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2001 Sep 
Date Detail:
Created Date:  2001-10-01     Completed Date:  2001-10-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1400-8     Citation Subset:  IM    
National Prion Disease Pathology Surveillance Center, Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
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MeSH Terms
Antioxidants / metabolism
Brain / metabolism
Metals / metabolism*
Osmolar Concentration
Oxidative Stress / physiology
PrPSc Proteins / metabolism
Prion Diseases / metabolism*
Prions / metabolism*
Superoxide Dismutase / metabolism
Reg. No./Substance:
0/Antioxidants; 0/Metals; 0/PrPSc Proteins; 0/Prions; EC Dismutase

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