Disease relevance of PRNP

• Immunologic and molecular biologic studies of prion proteins in bovine spongiform encephalopathy [1].
• Susceptibility to scrapie is largely controlled by the PRNP gene in mice and in several other species [2].
• The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, and the barriers limiting intermammalian transmission [3].
• We examined the ability of several recombinant antibody antigen-binding fragments (Fabs) to inhibit prion propagation in cultured mouse neuroblastoma cells (ScN2a) infected with PrPSc [4].
• Prions cause a group of human and animal neurodegenerative diseases, which are now classified together because their etiology and pathogenesis, involve modification of the prion protein (PrP) [5].

Psychiatry related information on PRNP

• All neuropathologically confirmed cases of variant Creutzfeldt-Jakob disease (vCJD), characterized by abundant florid plaques and type 4 disease-related prion protein (PrP(Sc)) in the brain, have been homozygous for methionine at polymorphic residue 129 of PRNP [6].
• It is thought that BSE is a result of cannibalism in which faulty industrial practices produced prion-contaminated feed for cattle [7].
• Gerstmann-Sträussler syndrome (GSS) was diagnosed in a family with presenile dementia by prion protein gene analysis [8].
• Prion dementia without characteristic pathology [8].

High impact information on PRNP

• We also carried out sequential knockout targeting of both alleles of a gene that is active in fibroblasts, encoding the bovine prion protein (PRNP), in the same genetic line to produce doubly homozygous knockout fetuses [9].
• Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals [3].
• The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns [3].
• Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein [3].
• We have now assessed whether expression of the cellular prion protein, PrPc, is required for B lymphocytes to mediate neuroinvasion [10].

Chemical compound and disease context of PRNP

• The profile of microglial changes induced by the CJD agent differed substantially from activation induced by bacterial lipopolysaccharide or by beta-amyloid, a structure comparable to pathological PrP [11].
• It is demonstrated here that a proline to leucine substitution in codon 168 of the ovine PrP protein gene is associated with increased resistance to experimental bovine spongiform encephalopathy (BSE) inoculation [12].
• In this article, we describe for the first time the use of streptomycin sulfate in IHC, providing a novel original and easy way to amplify specifically PrPsc immunohistochemical detection in natural cases of BSE and scrapie, as well as in experimental TSEs in mice models using two different PrP antibodies [13].
• The efficacy of three pretreatment techniques for the detection of prion protein (PrP) in formalin-fixed, paraffin-embedded bovine spongiform encephalopathy (BSE)--affected brain tissue were compared using automated image analysis [14].
• The conserved bovine prion protein 121KHVAGAAAAGAVVGGLGGYMLGSAMSR147 transmembrane region (BPrP(tm)) contains a sequence rich in Gly residues [i.e., 130GAVVGGLGGYMLGSAMSR147 (BPrP(mi))] that shows homology with HIV-1 fusion peptide [15].

Biological context of PRNP

• Frequencies of alleles and genotypes of the PRNP gene in Polish Red, Czech Pied and Czech Black-and-White cattle [16].
• We found 17 haplotypes for PRNP in the Caracu breed [17].
• A total of 10 single nucleotide polymorphisms (SNPs) were discovered in the coding region of the Caracu PRNP gene [17].
• The objective of this study was to identify polymorphisms and haplotypes within PRNP from the promoter region through the 3'UTR in a diverse sample of U.S. cattle genomes [18].
• This differential affinity could be explained by the existence of two binding sites within the PrP molecule [19].

Anatomical context of PRNP

• The level of nucleotide diversity in the complete bovine PRNP gene was pi = 0.00079, which is similar to that found at the bovine T-cell receptor alpha delta joining region (pi = 0.00077), but somewhat less than that observed for the bovine leptin (pi = 0.00265) [20].
• Role of microglia and host prion protein in neurotoxicity of a prion protein fragment [21].
• The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells [22].
• Cellular prion protein expressed by bovine squamous epithelia of skin and upper gastrointestinal tract [23].
• The presence of wild-type PrP molecules in the cytosol may have potential pathogenic implications [24].

Associations of PRNP with chemical compounds

• Analysis of the gene encoding bovine PRNP revealed homozygosity for alleles encoding 6 octapeptide repeats, serine (S) at codon 46, and S at codon 146 in all samples [25].
• Research over the past few years, however, demonstrates that the prion protein is a copper binding protein with high selectivity for Cu(2+) [26].
• Cells incubated with N-acetyl-leucinal-leucinal-norleucinal (ALLN), lactacystin or MG132 accumulated both detergent-soluble and insoluble PrP species [24].
• Short hairpin RNAs (shRNAs) were designed and screened for their ability to suppress the expression of caprine and bovine prion protein (PrP) [27].
• Evaluation of quinacrine treatment for prion diseases [28].

Other interactions of PRNP

• Significance and Impact of the Study: Toxoid preparations made from toxin produced with animal and dairy products can contain undesirable contaminants such as the prion causing bovine spongiform encephalopathy (Mad Cow's Disease) or antigenic peptides that stimulate anaphylactic reactions and other undesirable immune reactions in immunized hosts [29].
• The dorsal horns of the spinal cord in which BSE prion protein (PrP(BSE)) was deposited did not exhibit strong clusterin "up-regulation" but showed increased clusterin immunolabelling with a punctate distribution in the neuropil [30].
• This process may be considered as semi-conservative replication in which prion and lipids are analogous to the Watson and Crick strands and the proteolipid domain to the double helix itself [31].
• At 2 and 16 hours post stimulation 695 genes exhibited statistically significant differential expression, including; 26 sequences unique to the BoMP library, interleukin 6, prion protein and toll-like receptor 4 [32].

Analytical, diagnostic and therapeutic context of PRNP

• Molecular cloning of the bovine PrP gene showed that it encodes a protein of 256 or 264 amino acids with five or six Gly:Pro-rich octarepeats, respectively, in contrast to all other mammalian PrP genes, which encode only five octarepeats [1].
• Comparative sequence analysis and expression of bovine PrP gene in mouse L-929 cells [33].
• The expression level of recombinant bovine PrP in the cells judged by immunofluorescence was higher than that of authentic mouse PrP [33].
• In accordance with the lack of an interspecies barrier to BSE infection, we detected the typical signs of CNS spongiform degeneration by histopathological analysis and the presence of the bovine prion PrP(res) by Western blot or immunohistochemical analyses [34].
• The recent discovery of significant associations between bovine spongiform encephalopathy (BSE) susceptibility in German cattle and the frequency distributions of insertion/deletion (indel) polymorphisms within the bovine PRNP gene prompted an evaluation of 132 commercial U.S. artificial insemination (AI) sires from 39 breeds [35].

References