Normal prion protein is secreted from the endoplasmic reticulum through the Golgi apparatus into the plasma membrane where it is anchored to the surface by a glycosylphosphatidylinositol anchor (GPI-anchor). Normal prion proteins are also made naturally in the brain, however their usual use positive use has not been determined so they can still cause disease when they come into contact with an infectious form of the protein (PrPSc) making unusual forms. A prion is completely composed of protein and have no nucleic acid (in this way they are distinct from bacteria and viruses) and causes the transmissible spongiform encephalopathies in mammals including cattle and humans Scrapie is found in cattle, predominantly in sheep with a presumed origin of Skagafjör°ur around the 1880, confined to a parts of northern Iceland.
It is a fatal neurodegenerative disease. However in humans the disease is specifically known as Crentzdeldt-Jacob in humans, there are three types; genetic, sporadic and infectious. and bovine spongiform encephalopathy in cattle. Non infectious prion proteins found in the brain may help cause Alzheimer's disease. Mutations in the 102nd codon have been linked to neurodegeneration, which is the main, encompassing attribute of the prion diseases. Symptoms of these diseases include loss of motor control, paralysis, dementia, pneumonia and death. There is approximately one case per one million people a year and the average age of onset is usually 60-65 years and the average duration of the illness is approximately 7-8months and leads to death.
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Natural prion proteins produced in the brain interact with the amyloid-β peptides and predominantly α-helical forms to a β-sheet rich isoform (PrPSc) which seemingly cause transmissibility and pathogenesis.
The cellular prion protein (PrPC), is a copper binding protein and is located mostly at the,it has a primary role in the pathogenesis of prion disease such as BSE (bovine spongiform encephalopathy) and Creutzfeldt-Jakob disease. However, the physiological function of PrPC remains unknown. Cell culture and in vivo experiments by Mitteregger et al 2007, have indicated that PrPC and in particular its copper binding N-terminal octareat region are involved in neuroprotective and oxidative stress reactions. Changes in copper and manganese have been seen in infected brain tissues. Giese et al, 2004, in a confocal single molecule detection system found a specific pro-aggregatory effect of Mn2+ blocked by Cu2+ ions but could be reversed by+ EDTA, showing Mn2+ induces a reversible intermolecular binding with PrPC, while Cu2+needs strong binding to histidine containing binding sites, affecting structure and susceptibility of PrPC and its ability to aggregate (Levin et al 2005). However, experiments into the relationship between copper and PrPSc formation are inconclusive.
Normal prion protein (PrPc) High Mn concentration could hypothetically increase the attachment of the prion protein (PrPc and PrPsc) to cell membranes in the gastrointestinal tract and thus retard, or prevent, their entry through the mucosal epithelium. This idea gains in essence support from previous work showing that glycosylation of the prion protein has a kind of protective effect on its conversion to the pathological protein (PrPsc).
Prions disease alters brain structure and other nerves. Prions resist activation by procedures which modify nucleic acid and are immune to radiotherapy. Kuru is also another form of prions disease that first appeared in the early 1900s in New Guinea. It is not a genetic disorder as it was first thought by scholars in South Fore.
Chronic wasting disease (CWD) is a sporadic prion disease of deer and elk found in specific parts of America. The nature of the pathology is similar to spongiform degeneration caused by the lack of copper. The soil in regions where CWD is high have a deficiency in copper, insinuating the direct link between a lack of copper and CWD therefore disease is thought to be related to copper deficiency. This can be confirmed by immunodetection of PrP it is possible that copper deficiency may cause prion disease . However there is no definitive evidence
Prion related protein (PrP) is a glycoprotein which is causes some of the transmissible encephalopathies when misfolded. This misfolding is influenced by metal ions which also influences oligomerization, aggregation and fibril formation. Copper binding causes structural changes in the cellular isoform of PrP indicating that the misfolding and fibrilization may be caused by the presence of Cu2+ ions. Copper has been show to induce endocytosis of PrP, but levels of PrP do not seem to affect copper transportation.
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Thus the role of Cu2+ in the pathogenesis of previous termprion diseasenext term seems to be rather complex. Cu2+ may change the structure and of PrPC and also affect cell signalling and molecular mechanisms. However a higher availability of copper may cause oxidative stress conditions that generate an increase of PrPC with converting ability.
Hornshaw et al. , using circular dichroism (CD) spectroscopy, showed the secondary structure of PrP synthetic peptides corresponding to the octapeptide repeats were significantly modified by Cu2+.
Interestingly, PrP mutations that have several additional copies of the octapeptide repeat have been described in human genetic TSE forms. Such mutated molecules acquire biochemical properties similar to PrPSc and have an altered response to copper and induces neurodegeneration and spongiform change in transgenic mice This brings up the possible role of metal ions in the physiopathology of TSEs. metal ions like copper, manganese and zinc and their chelators affect the biochemical properties of PrPSc, possibly by changing the metal-ion availability of the molecule, resulting in a change in its mobility in denaturing electrophoresis, suggesting that metal-ion space shows the difference between prion strains and more generally in the differences between PrPC and PrPSc because Mn2+ cannot, at variance with Cu2+, be reduced but only oxidized. PrPSc binds manganese or zinc, instead of copper and therefore does not fit with the role of Cu2+ in the proper renaturation of PrPSc after unfolding in guanidine it has been shown that PrP acquires a partial protease resistance when incubated with Mn2+ or Zn2+ could represent intermediates in the generation of PrPSc, but have never been demonstrated to be infectious. Cu2+ could also cause in PrPC, a resistance to protease with a final conformation different from that of PrPSc
Equilibrium dialysis experiments using a recombinant fragment of PrPc equivalent to the N-terminal region of the protein to amino-residue 98 shows the region containing the octameric repeats could bind several atoms of copper.
Copper may bind to recombinant prion proteins and the affinity constant for copper binding is in the micromolar range, suggesting the affinity is rather low. Recent data suggest that prion protein cannot be isolated without at least one atom of copper bound per molecule (D. R. Brown, unpublished observations). During translation of PrP from its mRNA in the cell, the N-terminus may be placed in an environment where its affinity for the first previous termcoppernext term atom is enhanced or its binding is facilitated. Analysis of PrP related copper uptake by cells suggests that the Km for PrP facilitated copper uptake is in the nanomolar range which would suggest an affinity of 10−9 M or less placing copper binding by the prion protein in an acceptable range.
Thinking about the different studies that have been carried out on the effects of PrP on copper and why they bind, all from credible sources which have been discussed about. However transportation of the copper seems like the most credible explanation. Copper ions have also been said to increase accumulation of total PrP and inhibit the accumulation of PrPSc
15. D.R. Brown, previous termPrionnext term protein expression aids cellular uptake and veratridine-induced release of previous termcopper.next term J. Neurosci. Res. 58 (1999), pp. 717-725. View Record in Scopus Cited By in Scopus (82)Thackray et al. Investigated that if there were changes in trace elements in the brain, and other organs, of mice infected with mouse scrapie. He found changes in the levels of copper and manganese in their brains, before the onset of clinical symptoms. a reduction in brain copper and high levels in the liver and blood is observed, suggesting a displacement of copper from the brain. Changes in manganese were widespread, with higher levels occurring in blood, brain and muscle. He also found that brain manganese is increased relative to the decrease in copper. The change reached its maximum at the onset of clinical signs.
It has been suggested that prions are antioxidant proteins. Therefore, investigations were carried out on whether there were also changes in antioxidant proteins associated with disease progression. Even though expression levels of both copper zinc-superoxide dismutase (SOD) and manganese-SOD are not affected by prion disease the activity of the enzymes is affected. PrPC is believed to have a catalytic activity similar to SOD, which is a copper-dependent enzyme. The metal level of PrP-dependent SOD activity in purified proteins was also assessed. During infection, inoculated mice had a loss of bound copper and an increase in manganese. They also have a significant decrease in SOD-like activity. The decrease in activity are related to the decrease in copper, portraying a reduction in copper and antioxidant activity of the total PrP content. Manganese binding to PrPC is shown to stimulate its conversion into an abnormal conformation rich in β-sheets, and it is stipulated that an imbalance in brain trace elements could lead to the formation of PrPSc.
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Another study suggests that scrapie-induced prion disease may cause a change in the brain, and therefore a metal imbalance which could induce conversion of PrPC into PrPSc. Thackray et al. therefore postulates that changes in trace-element metabolism coming from changes in metal binding to PrP are important 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.