Disease relevance of PRPC

• Amino acid polymorphisms of the prion protein (PrP) gene (PRNP), particularly those occurring at codons 136, 154, and 171 have a significant influence on scrapie pathogenesis in many sheep breeds [1].
• Oral contamination with bovine spongiform encephalopathy (BSE) agent in susceptible PRNP genotype sheep results in widespread distribution of prion in the host [2].
• Further study of this second step may provide a future tool to determine the mechanism underlying refolding of PrPC into PrPSc and supports the use of conversion-resistant polymorphic PrPC variants as a potential therapeutic approach to interfere with PrP conversion in transmissible spongiform encephalopathy development [3].
• Transmissible spongiform encephalopathies (TSEs) are infectious, fatal neurodegenerative diseases characterized by aggregates of modified forms of the prion protein (PrP) in the central nervous system [4].
• Brains affected by the progressive neurological disease bovine spongiform encephalopathy (BSE) contain scrapie-associated fibrils and the protease-resistant isoform of prion protein [5].

Psychiatry related information on PRPC

• BACKGROUND: In sheep, susceptibility to scrapie, which is similar to human prion diseases such as Kuru and variant Creutzfeldt-Jakob disease (vCJD), is determined by prion protein (PrP) gene (Prnp) polymorphisms [6].
• Furthermore, in vitro conversion reactions with different prion strains revealed that the degree of alteration of the conversion efficiency induced by amino acid exchanges was varying according to the prion strain [7].
• TSEs are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination due to the accumulation of an abnormal isoform (PrP(Sc)) of the host-encoded prion protein (PrP(c)) [8].
• In an immunohistochemical study of naturally-occurring and experimental scrapie in sheep, deposits of cerebrovascular amyloid were found to react with antibodies to hamster scrapie prion protein (PrP 27-30), but not with antibodies to the amyloid beta-protein of Alzheimer's disease [9].
• These findings indicate that cell biological properties of ovine PrP can vary with natural polymorphisms and raise the possibility that differential interactions of PrP variants with the cellular machinery may contribute to permissiveness or resistance to prion multiplication [10].

High impact information on PRPC

• Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins [11].
• These results provide the first evidence that prion proteins assemble into filaments within the brain and that these filaments accumulate in extracellular spaces to form amyloid plaques [12].
• Because variant Creutzfeldt-Jakob disease (vCJD) in humans probably results from consumption of products contaminated with tissue from animals with bovine spongiform encephalopathy, whether infectious prion protein is present in ruminant muscles is a crucial question [13].
• Here we show that experimentally and naturally scrapie-affected sheep accumulate the prion protein PrP(Sc) in a myocyte subset [13].
• Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells [14].

Chemical compound and disease context of PRPC

• The cellular prion protein (PrPC), a membrane glycoprotein anchored to the outer surface of neurons, lymphocytes and other cells, is associated directly with the pathogenesis of the transmissible spongiform encephalopathies (TSEs) occurring mainly in humans, cattle, sheep and goats [15].
• We isolated blood samples from 222 sheep representing the eight main local sheep breeds in the Xinjiang Autonomous Region, the territory with the most abundant local sheep breeds in China, to identify the PRNP polymorphisms and to determine whether these breeds were at risk for developing scrapie [1].
• We have cured the scrapie-infected, clonal SMB cell line with pentosan sulfate, stably re-infected it with a different strain of scrapie and shown that biological properties and prion protein profiles characteristic of each original strain are propagated faithfully in this single non-neuronal cell type [16].
• Scrapie in the U.S. Suffolk breed and in many breeds in Europe occurs in sheep homozygous for glutamine (171QQ), but rarely in sheep heterozygous for glutamine and arginine (171QR) or homozygous for arginine (171RR) at codon 171 of the PrP gene [17].
• To further identify the critical molecular components of the CJD agent, 120S infectious material with reduced prion protein (PrP) was treated with guanidine hydrochloride or SDS [18].

Biological context of PRPC

• Single nucleotide polymorphisms (SNPs) and haplotype alleles within the prion gene (PRNP) coding sequence of domestic sheep (Ovis aries) are associated with genetic predisposition to scrapie, a transmissible spongiform encephalopathy disease of sheep [19].
• Linkage disequilibrium across six prion gene regions spanning 20 kbp in U.S. sheep [19].
• Evaluation of associations between prion haplotypes and growth, carcass, and meat quality traits in a Dorset x Romanov sheep population [20].
• These results suggested that expression of the Sh/Mo PrP or Bo/Mo PrP transgenes does not confer susceptibility to sheep prions upon mice, and thus none of the Tg mouse lines could be a suitable model of sheep scrapie [21].
• Disease susceptibility is linked to polymorphisms in the normal prion protein gene that encodes the mammalian prion precursor [22].

Anatomical context of PRPC

• Cellular prion protein (Prp(C)) is a glycoprotein usually associated with membranes via its glycosylphosphatidylinositol (GPI) anchor [23].
• Dpl was upregulated in the central nervous system of two PrP-deficient lines of mice, as well as in prionless cell lines [24].
• Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells [14].
• The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases [14].
• These findings indicate that cerebral accumulation of PrPSc and its degradation products may play a role in the nerve cell degeneration that occurs in prion-related encephalopathies [25].

Associations of PRPC with chemical compounds

• The effect of the osmolyte trimethylamine N-oxide on the stability of the prion protein at low pH [26].
• A new PRNP polymorphism encoding either glycine (G) or arginine (R) at codon 85 as well as eight previously reported polymorphisms at codons 101, 112, 127, 141, 146, 154, 171, and 189 in other sheep breeds were detected [1].
• Probing the dynamics of prion diseases with amphotericin B [27].
• Raman optical activity demonstrates poly(L-proline) II helix in the N-terminal region of the ovine prion protein: implications for function and misfunction [28].
• Prion diseases: what is the neurotoxic molecule [29]?

Regulatory relationships of PRPC

• Polymorphisms of the prion protein gene PRNP have been shown to influence the susceptibility/resistance to prion infections in human and sheep [30].

Other interactions of PRPC

• Various data indicate that the polymorphisms within the open reading frame (ORF) of PrP are associated with the susceptibility and control the species barrier in prion diseases [31].
• Eyes, optic nerves and brain from each animal were fixed and histologically processed using hematoxylin-eosin, followed by immunohistochemical staining for prion protein (PrPsc) and glial fibrillar acidic protein (GFAP) [32].
• In this report, we describe targeted deletion at the GGTA1 (alpha 1,3-galactosyl transferase) and PrP (prion protein) loci in primary fibroblasts from livestock [33].

Analytical, diagnostic and therapeutic context of PRPC

• Genotyping of ovine prion protein gene (PRNP) variants by PCR with melting curve analysis [34].
• Extracellular collections of abnormal filaments composed of prion proteins have been identified in the brains of scrapie-infected hamsters using immunoelectron microscopy [12].
• To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice into PrP-expressing mice and vice versa [14].
• Upon exposure to low doses of infectious agent, such cultures, unlike cultures originating from PrP null mice, were found to accumulate de novo abnormal PrP and infectivity, as assessed by mouse bioassay [35].
• Two Creutzfeldt-Jakob disease agents reproduce prion protein-independent identities in cell cultures [36].

References