Prion diseases or transmissible spongiform encephalopathy's can be inheritable and transmissible, the most common feature of a prion disease is the posttranslational conversion of the prion protein PrPc to the 'scrapie' isoform of prion protein PrPsc (Hur et al, 2007). Prion propagation involves the mechanism which converts PrPc to PrPsc in an autocatalytic fashion (Harris and tune, 2006).
Prion diseases can be characterised by spongiform changes for example neuronal loss and failure to induce an inflammatory response. Histologically the three major characteristics of prion diseases are neuronal loss, spongosis and gliosis, neuronal loss is particularly recognisable in the neocortex, the cerebellar cortex, the thalamus and the neostriatum and less likely to be found in the brain stem and hippocampus, spongosis is very frequent and found in the neocortex, basal ganglia, thalamus, hypothalamus and in the molecular layer of the cerebellum. (Mikol, 1999).
The PrPsc isoform is dominated by a beta sheet and is also resistant to digestion by protein kinase K, the PrPc form is monomeric, alpha helical and protease resistant (Harris and True, 2006). PrPsc can therefore accumulate in brain tissue of patients with prion diseases (Hur et al, 2007). All known prions induce the formation of an amyloid fold, the protein can polymerise into an aggregate consisting of tightly packed beta sheets, the beta sheets formed mean that this altered structure is more stable and can therefore easily accumulate in affected tissue causing tissue damage and also cell death.
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The cause of a prion disease is the prion protein, but the mutagenic form, the prion is an abnormal transmissible agent which is able to induce abnormal folding of normal cellular prion proteins in the brain. The prion hypothesis suggests that the agent is composed of a misfolded protein form PrPs of a normal cellular glycoprotein PrPc, the presence of PrPsc which can be detected after western blotting after digestion by protein kinase K (Yull et al, 2008).Different forms of prion diseases both human and animal forms are associated with different dorms of PrPsc.
Neurodegenerative diseases arise from misfolding and aggregation of a protein, the biological activity of a protein depends on its correct folding in the native conformation (Soto et al, 2002). During protein folding polypeptide chains form a 3D disulphide structure as directed by their amino acid sequences.
It has become increasingly clear that neurodegenerative diseases are caused by the misfolding of an otherwise normal protein and strong evidence has been shown that protein misfolding has a major role in TSE pathogenesis (Soto et al, 2002). One hypothesis proposes that the misfolded prion protein PrPsc is the sole component of the infectious agent aswell as being the most likely cause of the disease. A model for the conversion of PRPc to PrPSC shows that the pathological protein could act as a seed to recruit molecules with partially misfolded PrPc stabilising their misfolding by incorporating them in to an oligomer therefore the Prpsc oligomer is elongated at ends as new molecules of PrPc are converted and incorporated (Soto et al, 2002). A more general model of prion propagation proposed that the prion protein exists in equilibrium between a dominant PrPc and an essemble of minor conformations, one which can produce a stable oligomeric structure PrPsc, once a stable structure is formed PrP can now be assimilated in to a PrPsc aggregate, the amount of PrPsc which is deposited saturates normal cellular processors (Jackson, 1999).
The role of Prpc as an infectious agent and in the initiation of prion diseases is well known, however the biological function of this protein is less clear, it is highly expressed in the CNS and lymphoid organs therefore there is increasing evidence for the role of this protein in neurodevelopment and neuroprotection.
The biological role of the immune system is to defend organisms from pathogens within the innate immune system PrPc is expressed by many antigen presenting cells two of these included are dendritic cells and monocytes. However the functional role of the PrPc protein in the immune system remains unknown (Hur et al, 2007).
Since scrapie was found in sheep centuries ago various forms of prion diseases have been found.
Prion diseases include diseases in both humans and animals, disorders in humans include Creutzfeldt-Jakob disease,Kuru, Gerstmann Straussler-Scheinker disease and Fatal Familial insomnia and in animals such as scrapie in sheep, bovine spongiform encephalopathy(mad cow disease) in cattle, transmissible mink encephalopathy in mink, chronic wasting disease in deer and elk feline spongiform encephalopathy in cat, and also exotic ungulate encephalopathy in several exotic ungulates for example in Kudu (Hu et al,2002).
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Sporadic CJD is the most frequent type of prion diseases, histological lesions are those with predominance in the frontal temporal and parietal corticles. Cerebella amyloid plaques are present in ten percent of cases of the CJD prion disease (Mikol, 1999). The polymorphism of codon 129 has a major role in the phenotypic expression of CJD. Six to fifteen cases of CJD are familial CJD, this form of prion disease appears at a younger age and the duration is much longer, however the level of PrPres is much lower than in the sprodiac forms (Mikol, 1999). Both mutation and insertions have been found in the familial CJD prion disease. Mutation 178 is the most frequent and was shown in the first case of this disease found; the most frequent insertion is the insertion of 144 base pairs of the codon (Mikol, 1999). Fatal Familial insomnia is a very rare form of the prion disease and this is related to the mutation in codon 178 and also the polymorphism of codon 129, this form of prion disease is characterised by a selective atrophy and neuronal loss, histological lesions are found only when there is a high level of PrPres in the tissues and this increases with the duration of the diseases (Mikol, 1999). Gerstmann-straussler-scheinker disease is characterised by amyloid plaques in the molecular layer of the cerebellum and also in other parts of the brain, a mutation of codon 102 is common with this prion disease (Mikol, 1999). Kuru is an acquired form of the prion disease, lesions are dominant in the cerebellum and spongosis is present in the neocortex, lesions called 'Kuru plaques' are present in kuru and have been found in seventy percent of cases, these plaques increase along with the duration of the disease (Mikol, 1999). The new variant of CJD is said to be transmitted form bovine spongiform encephalopathy to humans. Plaques are found in this new variant form and are dominant in the cerebral cortex and in the cerebellar cortex, a high level of PrPres immunoreactivity had been found in the neocortex and in the molecular layer of the cerebellum (Mikol, 1999).
Prion diseases are characterised clinically by dementia, impaired motor function and neuropathologically by spongosis, amyloid deposition and neuronal loss (Harris and True, 2006).
Prion diseases have unusual properties in that they have extremely long incubation periods for a few months =s to maybe several years, there is also no inflammation connected ton these diseases (Hur, 2002). Prion diseases have become an important issue in public health and in the scientific world due to the unique biological features of the infectious agent and also due to the relationship between bovine spongiform encephalopathy and new variant CJD, evidence suggests that the abnormal form PrPsc may compose of substantial parts of the infectious agent and that certain factors such as oxidative stress and calcium cytotoxicity can be associated with the pathogenesis pf prion diseases (Hur et al, 2002).
Neuronal cell loss is thought to be a major cause of clinical symptoms in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and prion diseases,
There are any mechanisms of neurodegeneration in prion diseases (Hur et al, 2006).
Increasing evidence suggests that oxidative stress induced by reactive oxygen species and free radicals plays a role on the pathogenesis of prion diseases. Many oxidants are produced as by products in abnormal aerobic metabolism and are produced at a very high rate in neurodegenerative diseases, the CNS is extremely vulnerable to oxidative stress. Levels of MDA and H0-1 which are oxidative stress markers and generate free radicals which have been significantly increased in the brains of scrapie-infected mice (Hur et al, 2006). Oxidative stress induced by free radicals is associated with altered iron metabolism in neurodegenerative disorders, iron can aggravate oxygen toxicity. Iron in the presence of oxygen and hydrogen peroxide can be converted very easily in to more harmful species (Hur et al, 2002). There is increasing evidence that indicates that the alteration of calcium and related proteins plays a role in neuronal cell loss of neurodegenerative diseases including prion diseases, the PrP 106-126 a neurotoxic fragment of prion peptides is known to be involved in the regulation of intracellular calcium, the disturbance of calcium may contribute to the progressive neurodegeneration in the pathogenic process of prion diseases (Hur et al, 2002). The cellular and molecular aspects of the neuropathology of prion diseases suggest that some inflammatory elements such as pro-inflammatory cytokines and complement proteins may play an important role in deteriorating neuronal damage in prion diseases (Hur et al, 2002).
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The model of cell death for example necrosis or apoptosis in the pathogenic process of prion diseases is still unknown. Increased levels of calcium in mitochondria is a characteristic feature of necrosis, the observation that altered calcium metabolism in mitochondria can lead to mitochondrial dysfunction in scrapie infected animals supports the necrotic pathway of neurodegeneration in prion diseases (Hur et al, 2002).