Jakob and Other Prion Diseases

Creutzfeldt-Jakob and other prion diseases have been associated with disorders of copper metabolism. The first cases of Creuzfeldt-Jakob disease in humans were described by Creuzfeldt and Jakob over 80 years ago. Although scrapie was known as a fatal neurological 

An inevitable consequence of ageing is an elevation of brain iron in specific brain regions, e.g. in the putamen, motor cortex, pre-frontal cortex, sensory cortex and thalamus, localized within H- and L-ferritin and neuromelanin with no apparent adverse effect. However, ill-placed excessive amounts of iron in specific brain cellular constituents, such as mitochondria or in specific regions brain, e.g. in the substantia nigra and lateral globus pallidus, will lead to neurodegenerative diseases (Friedreich s ataxia and Parkinson s disease (PD), respectively). We discuss here a few of the examples of the involvement of iron in neurodegenerative diseases. From more on iron metabolism see Crichton, 2001. 

FIGURE 21.13 Schematic representation of the physiological role of prion protein (PrP°) in copper homeostasis and redox signalling. (From Crichton Ward, 2006.) 

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CREUTZFELDT-JAKOB DISEASE AND OTHER PRION DISEASES 662... 

Like any other protein, the molecular structure of the prion is subject to conformational flexibility and to various thermal-induced fluctuations between varying conformational states. However, if these fluctuations permit the PrP conformation to be attained, then this abnormal conformer promotes the widespread conversion of PrP to PrP , leading to the precipitous deposition of the abnormal protein throughout the brain (mirrored by the rapid and relentlessly downhill clinical course). This pathological self-propagating shape conversion of a-helical PrP to P-sheet PrP may in principle be initiated by a seed PrP molecule in the neurotoxic conformation. This explains the transmissibility of prion diseases and accounts for how susceptible humans exposed to beef from an animal with mad cow disease develop variant Creutzfeldt-Jakob disease. 

Many proteins can be made to clump into fibrous amyloid deposits like those seen in Alzheimer s disease, Creutzfeldt-Jakob disease (the human counterpart of mad cow disease), and other serious ailments. To help prove this point, a natural enzyme to convert to amyloid fibrils—insoluble protein aggregates with a /3-pleated sheet structure—simply by maintaining protein for some time in the unfolded state. Until now, scientists have generally believed that only specific proteins such as amyloid /3-protein and prions are capable of being converted into amyloid fibrils.11 A variety of spectroscopic techniques have been used to confirm the gradual development of amyloid fibrils and to verify the fibrils predominant /3-pleated sheet structure. In the partially unfolded intermediates that form under denaturing conditions, hydrophobic amino acid residues and polypeptide backbone normally buried inside fully folded structures become exposed. Further work is needed to confirm and advance these findings. 

In other acquired prion diseases, notably scrapie of sheep and variant Creutzfeldt-Jakob disease (vCJD) in humans, amino acids encoded at certain key positions in the endogenous host prion protein are strongly associated with susceptibility to prion infection [57-59]. Studies of CWD in elk, mule deer, white-tailed deer, and moose have found that similar correlations between PrP amino acid sequence and likelihood of CWD infection could exist in these species as well. 

Transmissible spongiform encephalopathies Prion-caused diseases resulting in brain tissue developing multiple holds such that it resembles a sponge, includes Creutz-feldt-Jakob disease, mad cow disease, kuru, scrapie and others. 

Another class of diseases is due to stmctural changes of proteins mediated by other molecules, so-called prions. As there is a strong causal coimection between the three-dimensional stracture of a protein and its biological function, refolding can cause the loss of functionality, A possible consequence is the death of cells. Examples for prion diseases in the brain are bovine spongiform encephalopathy (BSE) and its human form Creutzfeldt-Jakob disease (CID)." ... 

When a protein molecule gets misfolded for some reason, it is usually degraded. However, sometimes it escapes degradation and then it acts like a cheparon and causes the misfolding of the other protein molecules. This is the basis of the so-called infectivity of prions that causes mad cow disease and Creutzfeldt-Jakob disease. Once the healthy cow is exposed to misfolded protein or prions, it leads to the misfolding of the other proteins in the brain cells, which causes the disease. 

BSE) A degenerative disease of the brain that affects cattle and is caused by an abnormal form of a cellular protein (see prion). Known colloquially as mad cow disease , it results in a build-up of fibrous tissue in the brain. The infective agent can be transmitted to other cattle via feed containing offal derived from infected animals. It can also, under certain circumstances, be transmitted to other species. See also Creutzfeldt-Jakob disease. 

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