Introduction

Transmissible spongiform encephalopathies (TSEs) have cast a shadow of fear over the world especially for those who like a good piece of beef steak [1]. However, the reality of the variant Creutzfeldt-Jakob disease (CJD) epidemic is

Metal Ions in Life Sciences, Volume 1 Edited by Astrid Sigel, Helmut Sigel and Roland K. O. Sigel © 2006 John Wiley & Sons, Ltd that it has not happened [2]. Nevertheless, the possible transmission of a disease by a protein has sparked considerable interest in these diseases despite their very low occurrence. In addition the availability of animal models to study prion diseases has meant that they have become an exemplar for the study of neurodegenerative diseases in general [3].

The family of TSEs or prion diseases include both animal and human forms. The first studied human disease became known as Creutzfeldt-Jakob disease after the German neuropathologists who first described the changes in human patients [4]. Kuru, a disease of natives of New Guinea was linked to the consumption of human brain that carried CJD [5]. Eventually, inherited human prion diseases such as Gerstmann-Straussler-Scheinker syndrome [6,7] and fatal familiar insomnia were also described [8]. The inherited forms of disease are linked to point mutations or insertions in the gene that encodes the prion protein (prnp). The three most common animal forms of TSE are bovine spongiform encephalopthay (BSE) of cattle [9], scrapie of sheep [10] and chronic wasting disease (CWD) of deer and elk [11]. BSE is still widespread in Europe despite attempts to eradicate it by preventing cattle from eating possibly infectious food sources. The origin of BSE remains unknown and attempts to link it to scrapie have proven to be an inadequate explanation [12]. Similary, scrapie and CWD have no clear cause and appear to develop sporadically, often associated with particular environmental locations [13].

Experimental models of TSEs depend upon the inoculation of mice or hamsters with extracts from the brains of animals with one of the TSEs. This is therefore a form of experimental infection. Although such experimental transmission can occur in the laboratory, TSEs are not contagious diseases. Transmission between individuals largely does not occur, although it is possible that a small number of vCJD cases have been passed to other patients through blood transfusions [14]. CJD is the most common form of human prion disease. It is different to variant CJD in that this latter form affects mostly young people with a specific genotype. To date, all patients with vCJD have two copies of the 129Met (coding methionine at codon129) allele of prnp.

All prion diseases are linked to the deposition of an abnormal isoform of the prion protein in the central nervous system of the affected individual [3]. This abnormal isofrom (PrPSc) is accepted as the infectious agent of the diseases and is the probable cause of the pathology associated with the disease [15]. PrPSc is highly rich in P-sheet structure, is highly resistant to protease digestion and aggregates to form fibrils in vitro. Although central to the disease process, it is still not completely clear that this form of the protein is the one that can cause transmission of disease between individuals or that it is all that is essential for the disease. Without expression of the protein prion disease cannot develop because mice that have been transgenically altered to lack expression of PrP are resistant to TSEs [16]. The 'protein-only' hypothesis remains largely accepted and has been supported by recent studies that show that recombinant PrP can be used to initiate a prion-like disease in mice and that this new disease can be transmitted to other mice. Yet, other researchers still argue that the protein itself is insufficient for a true TSE.

Although it is unclear what exactly causes prion disease and the mechanism of conversion of the normal cellular isoform (PrPc) to PrPSc remains unde-scribed [17], recent research has made strong inroads into understanding the nature of the substrate for prion diseases, the normal isoform of the prion protein. PrPc is a glycoprotein [18] expressed by many cell types, but especially by neurons [19]. The protein is concentrated at synapses [20] and is therefore thought to have some special role in neuronal function. It is produced in cells as a single monomeric polypeptide of around 250 amino acids in length. The regulation of its expression is still poorly characterized, but it is highly regulated with not only a promoter, but also by regulator regions in exons 1 and 2 encoded by the messenger RNA that are not transcribed into protein [21]. The third exon of PrP encodes the whole open reading frame and contains highly conserved regions. Prion protein knockout mice develop normally and show little in the way of behavioral difference to wild-type [22]. Nevertheless, there have been a large number of reported differences in the mice and especially there are distinct difference in the response of neurons cultured from the brains of the mice. These differences suggest that PrPc aids to protect neurons from cellular responses to stress [23].

The essential requirement of host prion protein expression for both, the transmission of the disease and the triggering of neuronal death, implies that understanding the nature of the normal isoform of the prion protein is inseparable from discovering the mechanism of disease transmission and progression. The mechanism of conversion of the protein remains unknown, but is thought to involve the formation of seeds or small aggregates of PrP which can then catalyze rapid conversion to further host protein to the abnormal isoform. This issue is further complicated by the existence of strains [24]. Strains of prion diseases (especially scrapie) are characterized by different characteristics of the resulting disease when applied to the same species of host. Thus, the characteristics will remain the same when transmitted to different individuals of the same species of animal or even the same breed of mouse. These characteristics include location and severity of neuronal loss and gliosis, extent and location of PrPSc deposition, incubation time for the disease and duration of symptoms. These characteristics for BSE in cattle may change when the disease is transmitted to mice, but within mice or cattle the characteristics are the same in different individuals after subsequent passages. This secondary information suggests that if the protein is the sole cause of the disease, then somehow this is encoded by the way the conformation is altered during conversion of PrPc to PrPSc. There is currently no explanation for how this information could be encoded by the conformational change.

Prion diseases have only been identified in mammals. However, other vertebrates express homologues of PrP. These include birds, reptiles, amphibians and fish [25-29]. The sequences identified in reptiles and birds show very high homology to mammals, except that in the N-terminus mammals have four or more repeats of an octamer while birds and reptiles have five or more repeats of a hexameric region. Amphibians and fish express one or more homologues of PrP, but essential domains are quite different and it is unclear if these homologues would serve the same function in these lower vertebrates. The hexameric or octameric repeat regions are the suggested binding place for copper to PrPc. Investigation of the possible function of these regions leads to the suggestion that these sites could be copper bindings sites [30,31]. Early studies of peptides related to these regions were the first to demonstrate interaction of copper occurs at these sites. These findings triggered a wave of interest in the potential of PrPc to be a metalloprotein. This review will deal with current understanding of metal interactions with PrPc and their possible consequence for the function of the PrPc and disease progression in TSEs.

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