Prion protein encephalopathies

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. 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

The normal cellular form of prion protein (PrPc) can exist as a Cu-metalloprotein in vivo (492). This PrPc is a precursor of the pathogenic protease-resistant form PrPsc, which is thought to cause scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt—Jakob disease. Two octa-repeats of PHGGGWGQ have been proposed as Cu(II) binding sites centered on histidine (493). They lack secondary and tertiary structure in the absence of Cu(II). Neurons may therefore have special mechanisms to regulate the distribution of copper. 

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... 

With the background of the mad cow crisis in Europe, questions relating to the prion diseases have attracted intensive interest. It is now widely accepted that prion diseases, such as Creutzfeldt-Jakob disease (CJd) in humans and bovine spongiform encephalopathy (BSE) are caused by a conformational change of the prion protein (PrP) from a normally folded cellular form, PrP ", to an alternate, aggregation-prone, pathogenic scrapie form,... 

The prion protein (PrP) is an infectious protein that converts noninfectious PrP into the infectious form, which precipitates. PrP is implicated as the causative agent of the transmis sible spongiform encephalopathies, including Creutzfeld-Jakob disease. 

EMPs as Carriers of Molecules. In addition to measurable antigens, EMPs as other MPs, are also carriers of molecules. Conformationally changed prion proteins, believed to aid in the propagation of spongiform encephalopathies, have been detected on EMPs released by infected ECs [68]. This finding indicates that EMPs may be active players in the infectious process of spongiform encephalopathies. 

Spraker TR, Zink RR, Cummings BA et al (2002) Distribution of protease-resistant prion protein and spongiform encephalopathy in free-ranging mule deer (Odocoileus hemionus) with chronic wasting disease. Vet Pathol 39 546-556... 

Tamguney G, Miller MW, Giles K et al (2009) Transmission of scrapie and sheep-passaged bovine spongiform encephalopathy prions to transgenic mice expressing elk prion protein. J Gen Virol 90 1035-1047... 

Race RE, Raines A, Baron TG et al (2002) Comparison of abnormal prion protein glycoform patterns from transmissible spongiform encephalopathy agent-infected deer, elk, sheep, and cattle. J Virol 76 12365-12368... 

Scott MR, Safar J, Telling G, Nguyen O, Groth D, Torchia M, Koehler R, Tremblay P, Walther D, Cohen FE, DeArmond SJ, Prusiner SB (1997) Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. Proc Natl Acad Sci USA 94 14279-14284... 

Baron T, Crozet C, Biacabe AG, Philippe S, Verchere J, Bencsik A, Madec JY, Calavas D, Samarut J (2004) Molecular analysis of the protease-resistant prion protein in scrapie and bovine spongiform encephalopathy transmitted to ovine transgenic and wild-type mice. J Virol 78 6243-6251... 

Der Trab ist auch eine Krankheit der Schaafe, und ist ansteckend. Sie schleppen sich lange, verzehren sich nach und nach, und zuletzt miissen sie sterben. These sentences are taken from an article published in 1759 [1] and describe two hallmarks of prion diseases or transmissible spongiform encephalopathies (TSEs, summarized in Table 1) The formation and transmission of an infectious particle and the invariably fatal course of these diseases. More than 200 years later a landmark discovery paved the way to study the pathogenesis of prion diseases at a molecular level. Prusiner and colleagues reported the identification of a protease-resistant protein in brain extracts, which co-purified with the infectious scrapie agent [18]. After the N-terminal amino acid sequence of the proteinase K (PK)-resistant core of the prion protein (PrP 27-30) was published in 1984 [19], two... 

Chesebro B, Race B, Meade-White K et al (2010) Fatal transmissible amyloid encephalopathy a new type of prion disease associated with lack of prion protein membrane anchoring. PLoS Pathog 6 el000800... 

Bessen RA, Marsh RF (1992) Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 66 2096—2101... 

Riek R, Wider G, Billeter M, Homemann S, Glockshuber R, Wiithrich K (1998) Prion protein NMR structure and familial human spongiform encephalopathies. Proc Natl Acad Sci USA 95 11667... 

Nitrini R, Rosemberg S, PassosBueno MR, daSilva LST, Iughetti P, Papadopoulos M, Carrilho PM, Caramelli P, Albrecht S, Zatz M, LeBlanc A (1997) Familial spongiform encephalopathy associated with a novel prion protein gene mutation. Ann Neurol 42 138... 

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