Prion pathology

Prions—protein particles that lack nucleic acid— cause fatal transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease, scrapie, and bovine spongiform encephalopathy. Prion diseases involve an altered secondary-tertiary strucmre of a namrally occurring protein, PrPc. When PrPc interacts with its pathologic isoform PrPSc, its conformation is transformed from a predominantly a-helical strucmre to the P-sheet strucmre characteristic of PrPSc. 

Prion diseases resulting in encephalopathy can be transmitted between individuals within species (more rarely between species) [26-28], A conformational variant of the normal cellular protein PrPs (PrPc) (protease-sensitive or cellular) is believed to catalyze [29] or nucleate [30-33] conversion to the pathological form, PrPR (protease-resistant). This highly unusual nongenetic mode of transmission of an infectious agent has been strongly debated [29]. The observation of multiple examples of nucleated catalysis of aberrant polymerization of protein subunits has... 

Cohen FE, Prusiner SB. Pathologic conformations of prion proteins. Annu... 

Peripheral pathogenesis involves the lymphoreticular system 794 Prion disease produces characteristic pathology in the central nervous system 795... 

Peripheral pathogenesis involves the lymphoreticular system. Although the pathological consequences of prion infection occur in the central nervous system, and experimental transmission of these diseases is most efficiently accomplished by intracerebral inoculation, most natural infections do not occur by these means. Indeed, administration to sites other than the central nervous system is known to be associated with much longer incubation periods, which may extend to 20 years or more [5,12]. Experimental evidence suggests that this latent period is associated with clinically silent prion replication in... 

Pathological conditions are also linked to posttranslational modifications such as oxidized histidine residues found in P-amyloid protein of Alzheimer s patients, or conformational variants in the case of prion-induced encephalopathies. The development of sensitive MS tools and proteomics techniques is playing an active role in the precise description of these mechanisms.97,98... 

Protein aggregation is a hallmark of scrapie, and scrapie protein can be induced to aggregate in vitro into forms that are indistinguishable from pathological brain-derived fibrils. Prusiner proposed that prion disease involves a mechanism for autocatalytic conversion of a host... 

Prions, viruses, bacteria, fungi, parasites (pneumonia, meningitis, gastroenteritis) Neoplastic (pathology from tumors, cancer)... 

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. 

Prion diseases have attracted immense attention over the past decade, prompted, in part, by the outbreak of mad cow disease in the United Kingdom. The most common prion disease is sporadic Creutzfeldt-Jakob disease (CJD). Clinically, CJD is characterized by a rapidly progressive dementia accompanied variably by early-onset seizures, insomnia, disordered movements, and psychiatric disturbances the disease is uniformly fatal. Histochemically, the principal pathological feature of prion disease is the abnormal accumulation of an amyloid-like material composed of prion protein (PrP), which is encoded by a single gene on the short arm of chromosome 20. 

Recently, it has been ascertained that the pathologic self-assembly nature of inherent peptides or proteins is one major event that leads to the development of many diseases such as prion protein in prion disease, a-synuclein in Parkinson s disease, and islet amyloid polypeptide in type 2 diabetes, as well as Api-42 in AD (9). 

PrP " deposition in the central nervous system is also a hallmark feature of prion disease (Prusiner, 1991). The type of Prpsc cleposit and its location varies among the human prion diseases. PrP is also a component of amyloid plaques. A characteristic of vCJD and kuru is florid amyloid plaques, which is a large cluster of PrP aggregates interspersed with vacuolar pathology. PrP deposition is also present in peripheral tissues of patients with vCJD, primarily in secondary... 

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