NR AOOP
AU Attwood,T.K.
TI Metals in prion disease
QU Trends in Biotechnology 2002 Jun; 20(6): 235
PT Editorial
VT
Cellular prion protein (PrPc) is a cell-surface protein expressed mostly by neural tissue. Although its precise function is unknown, among the possibilities is a role in copper metabolism. An abnormal conformation of the protein (PrPsc) is believed to be the causative agent of prion diseases. These are fatal neurodegenerative disorders in which neuronal loss and overgrowth of glial fibres occur after long, seemingly asymptomatic, incubation periods. It seems that expression of PrPc is necessary for the manifestation of prion disease, as genetically modified mice that fail to express it are resistant to infection with mouse prion inoculum. However, exactly how the conformational change from PrPc to PrPsc leads to neurodegeneration is not understood.
PrPc is a copper-binding protein. To further elucidate the role of metals in prion disease, Thackray et al.[1] investigated whether there were changes in trace elements in the brains, and other organs, of mice infected with mouse scrapie. Interestingly, the authors found changes in the levels of copper and manganese in the brains of infected mice, prior to the onset of clinical symptoms. Specifically, they observed a reduction in brain copper and significantly elevated levels in the liver and blood, suggesting a displacement of copper from the brain or other tissues. Changes in manganese were more widespread, with elevated levels occurring in blood, brain and muscle. Of particular note was the increase in brain manganese relative to the decrease in copper. The change reached its maximum at the onset of clinical signs. This constitutes the first report of a neurodegenerative disease in which there is a systemic change in manganese, perhaps signifying a characteristic that will allow selective diagnosis of prion disease.
It has been suggested that prions are antioxidant proteins. Therefore, the authors investigated whether there were also changes in antioxidant proteins associated with disease progression. They found that whereas expression levels of both copper/zinc-superoxide dismutase (SOD) and manganese-SOD are not altered by prion disease, the activity of the enzymes is affected. Both purified and recombinant PrPc are believed to have a catalytic activity similar to SOD, which is a copper-dependent enzyme. The metal content and level of PrP-dependent SOD activity in purified proteins was therefore assessed. During infection, inoculated mice showed a loss of bound copper and an increase in associated manganese, together with a significant decrease in SOD-like activity. The decrease in activity matched the decrease in copper, implying a reduction in copper and antioxidant activity of the total PrP content. Manganese binding to PrPc is known to stimulate its conversion into an abnormal conformation rich in ß-sheets, and it was thought that an imbalance in brain trace elements could lead to the formation of PrPsc.
This study suggests that scrapie-induced prion disease might cause such a change in the brain, and therefore a metal imbalance could induce conversion of PrPc into PrPsc. Thackray et al.therefore postulate that alterations in trace-element metabolism arising from changes in metal binding to PrP are central to the pathological modifications characteristic of prion disease. Further analysis of the alterations are necessary, but the implication is that these values might represent specific changes with immediate diagnostic potential.
1 Thackray, A.M. et al.(2002) Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem. J. 362, 253-258
AD Teresa K. Attwood, attwood@bioinf.man.ac.uk
SP englisch
PO England
OR Prion-Krankheiten 1