Disease relevance of Prnp

• IgG immunostaining revealed that in Prnp-/- mice the breakdown in the blood-brain barrier (BBB) was more extensive at 1 month after brain injury [1].
• After inoculation with hamster scrapie, these mice accumulated infectivity and PrPSc to high levels, developed severe disease after 227 +/- 5 days and died 7 +/- 4 days later [2].
• Transmissible spongiform encephalopathies are characterized by spongiosis, astrocytosis and accumulation of PrPSc, an isoform of the normal host protein PrPC [2].
• Absence of the prion protein homologue Doppel causes male sterility [3].
• The appearance of the novel acquired prion disease, variant Creutzfeldt-Jakob disease (vCJD), and the demonstration that it is caused by the same prion strain as that causing bovine spongiform encephalopathy, has led to fears of a major human epidemic [4].
• The PrP-induced myopathy correlates with accumulation of an N-terminal truncated PrP fragment in the muscle, and the muscular PrP displayed consistent mild resistance to protease digestion [5].
• Formation of PrP amyloid may therefore not necessarily be a reliable marker of transmissible spongiform encephalopathy infectivity [6].

Psychiatry related information on Prnp

• Variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to prions, and exhibit early prion accumulation in germinal centers [7].
• As for cerebral amyloidoses, although the correlation between amyloid beta protein (Abeta) and apoE in Alzheimer's disease (AD) has been clarified, the interaction of prion protein isoform (PrPsc) and apoE in several types of prion diseases (PDs) has not been examined in detail [8].
• Transgenic Tg(PG14) mice express a mutant prion protein containing 14 octapeptide repeats, whose human homologue is associated with an inherited prion dementia [9].
• After the sleep deprivation, SWA was increased, but the changes in EEG power density and SWA were more prominent and lasted longer in the PrP-null mice [10].
• PrP mutant T182N/T198A also provoked a strong dominant-negative inhibition on the endogenous wild type PrP conversion reaction [11].

High impact information on Prnp

• Classical genetic analysis has identified Sinc/Prni as the major gene controlling mouse scrapie incubation time [12].
• Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions [13].
• Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein [14].
• Here we demonstrate that this PrP null phenotype is rescued in mice with a high copy number of a transgene encoding human PrP but not in low copy number mice, confirming the specificity of the phenotype for loss of function of PrP [14].
• PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor-mediated fast inhibition and impaired long-term potentiation in the hippocampus [14].

Chemical compound and disease context of Prnp

• Mild formaldehyde crosslinking of mouse neuroblastoma cells (N2a) that are susceptible to prion infection revealed the presence of PrP(C) in high molecular mass (HMM) protein complexes of 200 to 225 kDa [15].
• Overexpression of PrPC by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrPC-Flag into ischemic rat brain improved neurological behavior and reduced the volume of cerebral infarction, which is supportive of a role for PrPC in the neuroprotective adaptive cellular response to ischemic lesions [16].
• Neither detergent (2% Sarkosyl) extraction nor limited proteinase K digestion of scrapie microsomes produced recognizable prion amyloid rods [17].
• More strikingly, cellular MTT formazan exocytosis revealed the formation of bioactive amyloid species in prion-infected mouse N2a neuroblastoma cells [18].
• We used wild-type mice, PrP knockout (Prnp(-/-)) animals and transgenic mice that lack the octarepeat region (C4/-) and subjected them to controlled ischemia [19].

Biological context of Prnp

• The interaction between the Prnp and Prnd genes in mouse cerebellar neurons may have a physical correlate in competition between Dpl and PrP(C) within a common biochemical pathway that when mis-regulated leads to apoptosis [20].
• Remarkably, Dpl-programmed ataxia is rescued by wild-type Prnp transgenes [20].
• However, little is known about the cell death of Prnp(-/-) neuronal cells under serum deprivation [21].
• We conclude that the new allele, Prnp(c), modulates incubation time but not neuropathology and that the previous classification of mice into two distinct groups based on incubation time and Prnp genotype should now be revised [22].
• The reverse transcription polymerase chain reaction revealed that serum deprivation did not increase Prnp/Prnd chimeric mRNAs, which in fact was translated into a small amount of Dpl in HpL3-4 cells, whereas serum deprivation induced apoptotic cell death of HpL3-4 cells [23].

Anatomical context of Prnp

• Here we report torpedo-like axonal swellings associated with residual Purkinje cells in Prnp o/o mice, and we demonstrate abnormal myelination in the spinal cord and peripheral nerves in mice from two independently established Prnp o/o lines [24].
• By Northern blot analysis, two kinds of Prnp transcripts (major band of 2.2 kb, and minor band of 1.1 kb) were detected in testes [25].
• These results suggest that Prnp may be involved in germ cell differentiation during mammalian spermatogenesis [25].
• In situ hybridization analysis showed that the positive signals for Prnp mRNAs were predominantly observed in spermatogenic cells, but not in somatic cells such as Sertoli cells, Leydig cells and peritubular myoid cells [25].
• To determine the possible role of astrocytes, we generated mice devoid of murine PrP but expressing hamster PrP transgenes driven by the astrocyte-specific GFAP promoter [2].

Associations of Prnp with chemical compounds

• Mice lacking the cellular prion protein (PrP(c)) gene (Prnp) present a decreased astrocytic glutamate uptake in cultures, higher neuronal excitability in vitro and sensitivity to pro-convulsant drugs in vivo, and age-dependent memory impairment [26].
• A common human prion-protein-gene (PRNP) polymorphism (encoding either methionine or valine at codon 129) is a strong susceptibility factor for sporadic and acquired prion disease [4].
• A cell model which was previously established from Rikn mice (PrP-/-) remains problematic because of its ectopic expression of the doppel (Dpl) which may have a neurotoxic effect [27].
• In addition, Ca(2+) levels of mitochondria were increased, whereas mitochondrial membrane potentials were decreased in PrP(-/-) cells [28].
• Combined, ultrastructural and thioflavin assays, together with microglial cytokine release measurements, provide a test system to screen potential, fibrillarity impeding therapeutics for prion disease [29].
• Mutations within PrP 98-110, substituting all 4 wild-type lysine residues with alanine residues, prevented conversion to PrP(Sc) [30].

Physical interactions of Prnp

• We established the linkage relationship between the prion gene complex (Prn) and other chromosome 2 genes; the gene order, proximal to distal, is B2m-II-1a-Prn-Itp-A [31].
• Additionally, similar levels of PrP/N-CAM complexes were found in N2a and prion-infected N2a (ScN2a) cells [15].
• In this configuration, C1q bound avidly to PrP, with a K(D) of 5.4 nM (k(on) = 2.4 x 10(5) M(-1) s(-1); k(off) = 1.3 x 10(-3) s(-1)) [32].
• The cellular prion protein (PrP) selectively binds to Bcl-2 in the yeast two-hybrid system [33].
• Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery [34].

Co-localisations of Prnp

• The cellular prion protein colocalizes with the dystroglycan complex in the brain [35].

Regulatory relationships of Prnp

• These results indicate that prion replication triggers an abnormal localization of caveolin 1 and synaptophysin, which in turn may alter neuronal function [36].
• Prion-induced amyloid heart disease with high blood infectivity in transgenic mice [37].
• Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC [38].
• NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells [39].
• Here, a single treatment with LT beta R-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of infectivity and disease-specific PrP (PrP(Sc)) within the spleen and substantially reduced disease susceptibility [40].

Other interactions of Prnp

• Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth [41].
• These findings raise the possibility that the cells of the molecular layer express an auxiliary protein, provisionally designated protein X, which is involved in prion formation and is likely to be distinct from the protein that mediates Dpl-induced degeneration [42].
• These phenomena, together with the founder effect, would favor apparent linkage disequilibrium between Prn-p and Prn-i. Therefore, transmission genetics may underestimate the number of genes in Prn [31].
• Recombination suppression in the B2m-Prn-p interval occurred during the crosses involved in transferring the I/LnJ Prnb complex into a C57BL/6J background [31].
• Probing the conformation of the prion protein within a single amyloid fibril using a novel immunoconformational assay [43].

Analytical, diagnostic and therapeutic context of Prnp

• Here, we show for the first time that different signal transduction pathways are involved in neurite outgrowth and neuronal survival elicited by PrP in cell culture of primary neurons [44].
• Neural antigen density of prion protein, Thy-1 and glial fibrillary acidic protein was analyzed using flow cytometry of dissociated mouse brain cells after inoculation with mouse-adapted transmissible spongiform encephalopathy agents [45].
• Intracerebroventricular delivery of dominant negative prion protein in a mouse model of iatrogenic Creutzfeldt-Jakob disease after dura graft transplantation [46].
• METHODS: Western blot, immunohistochemical detection, and RT-PCR methods were used to identify and quantitate prion protein expression in human, monkey, and guinea pig lenses [47].
• Western blot analysis showed that PrPC protein expression increased in ischemic brain tissue in a time-dependent manner [16].

References