Review of Prion Science, by Dr. DR Brown, UK

[Kathy]

This is a new publication by Dr. David R. Brown at the University of Bath, UK.(1)

The research paper after, was conducted by Brown, BS Wong et al on the metal imbalances found in the brains of patients that had died of sporadic CJD in 2001.(2)

(1)Folia Neuropathol. 2005;43(4):229-43. Links

Neurodegeneration and oxidative stress: prion disease results from loss of antioxidant defence.
Brown DR.

Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, e-mail: [email protected].

Prion diseases or transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that can be acquired either by direct transmission, inherited through dominant mutations in the prion protein gene or via an unknown sporadic cause. This latter group constitutes the vast majority of cases. Like many neurodegenerative diseases the hallmarks of oxidative damage can be readily detected throughout the brain of the affected individual. However, unlike most other neurodegenerative diseases, prion diseases are connected with a dramatic loss of antioxidant defence. As abnormal protein accumulates in the diseased brain there is both an increase of oxidative substances and a loss of the defences that keep them in check. In particular the normal cellular prion protein has been shown to be an antioxidant. Conversion of this protein to the protease resistant isoform is accompanied by a loss of this antioxidant activity. This change creates a paradox as the loss of activity is not accompanied by a loss of protein expression. It is likely that this prevents other cellular defences from responding sufficiently to protect neurons from the heightened oxidative burden. Recent experiments with transgenic mice have shown that when prion protein expression is switched off during the course of prion disease, cell death is dramatically halted and the mouse recovers from the disease. This result clearly illustrates that the continued expression of non-function prion protein is essential for disease progression. This implies that the presence of this abnormal protein during prion disease causes a failure of cellular antioxidant defence. This failed defence is the fundamental cause of the massive neurodegeneration that results in the fatal nature of TSEs. The role of oxidative stress in TSEs and other neurodegenerative disorders are discussed in this review.

(2)J Neurochem. 2001 Sep;78(6):1400-8. Related Articles, Links

Aberrant metal binding by prion protein in human prion disease.

Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR.

National Prion Disease Pathology Surveillance Center, Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

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.