Disease relevance of Prnp

• The pathological conversion of cellular prion protein (PrP(C)) into the scrapie prion protein (PrP(Sc)) isoform appears to have a central role in the pathogenesis of transmissible spongiform encephalopathies [1].
• Conversion of the normal cellular prion protein (PrPc), whose physiological function is still under investigation, to an infectious form called prion is the cause of some neurodegenerative diseases [2].
• Its efficiency could be shown by the successful synthesis of the GPI anchor of rat brain Thy-1 and of the scrapie prion protein both in the water soluble 1c and lipidated form 1a [3].
• In contrast, rat B104 neuroblastoma cells abundantly expressed N-glycosylated cellular prion protein forms similar to those observed in mouse and rat brain [4].
• Mouse hypothalamic GT1-7 cells and rat pheochromocytoma PC-12 cells expressed highly glycosylated forms of cellular prion protein that were found neither in adult mouse and rat brain, nor in mouse brain during development [4].

Psychiatry related information on Prnp

• By analogy with the pathological events occurring during the development of Alzheimer's disease, controversies still exist regarding the relationship between amyloidogenesis, prion aggregation, and neuronal loss [5].
• The data show a remarkable consistency in the concurrence of a single peak of prion protein messenger RNA at each of the sites early in the animal's phase of increased locomotor activity; behavioural arousal does not, however, appear to affect this expression [6].
• The infectious prion protein (PrPSc) is the etiologic agent of transmissible neurodegenerative conditions such as scrapie or Creutzfeldt-Jakob disease [7].

High impact information on Prnp

• Furthermore, both the complementary prion peptide and antiserum against it inhibit the toxicity of a prion-derived peptide toward neuronal cells in culture [8].
• A specific cell-surface receptor to mediate PrPC and prion endocytosis has been predicted [8].
• The complete change in phenotype achieved by transferring a prion determinant from one protein to another confirms the protein-only nature of prion inheritance and establishes a mechanism for engineering heritable changes in phenotype that should be broadly applicable [9].
• Developmental expression of the prion protein gene in glial cells [10].
• We report here that PrP mRNA is expressed not only in neurons but also in astrocytes and oligodendrocytes throughout the brain of postnatal hamsters and rats [10].

Chemical compound and disease context of Prnp

• These results suggest that the beta-sheet and amyloid structures of the prion peptides give rise to their toxicity and membrane binding affinities and that membrane binding affinity, especially in cholesterol-rich environments, may be related to toxicity [11].
• Suramin induces misfolding of the cellular prion protein (PrP(C)) and interferes with the propagation of infectious scrapie prions [12].
• Myoblasts and myotubes are resistant to the toxicity of a neurotoxic prion protein peptide (PrP106-126) [13].
• During these diseases a cellular glycoprotein (the prion protein, PrP(C)) is converted, through a not yet completely clear mechanism, in an altered isoform (the prion scrapie, PrP(Sc)) that accumulates within the brain tissue by virtue of its resistance to the intracellular catabolism [14].
• Production of PrionSc in the Scrapie prion-infected subclone of N2 a cells (ScN2 a cells) was not affected by memantine [15].

Biological context of Prnp

• The MTF-1-independent transcriptional activation of Prnp is supported by the lack of Prnp promoter activation by zinc [16].
• Biotinylation experiments indicated that almost all prion protein recovered in this fraction was exposed at the cell surface [17].
• To test for a role for the cellular prion protein (PrP(c)) in cell death, we used a PrP(c)-binding peptide [18].
• We have investigated the organization, on the plasma membrane and in detergent-insoluble membrane vesicles, of two neuronal glycosylphosphatidylinositol-anchored (GPI) proteins: Thy-1, a negative regulator of transmembrane signalling; and prion protein, whose rapid endocytosis and Cu(2+) binding suggest that it functions in metal ion uptake [19].
• Regulation of the cellular prion protein gene expression depends on chromatin conformation [2].

Anatomical context of Prnp

• In addition, copper induced the activity of a reporter vector driven by the rat PrPC gene (Prnp) promoter stably transfected into PC12 cells, whereas no effect was observed in glial C6 clones [16].
• Thus, prion protein plasma membrane environment in differentiated neurons resulted to be a complex entity, whose integrity requires a network of lipid-mediated non-covalent interactions [17].
• Among the proteins and lipids present in detergent-resistant fractions, almost all Prion protein, GAP43 and PKC were present in the immunoprecipitate obtained with anti-GAP43 or anti-Prion protein antibody at 4 degrees C, together with a small fraction of cholesterol and sphingolipids, suggesting that they belong to a distinct subset of membranes [20].
• To address this issue, we have been using cultured cells to analyze the localization, biosynthesis, and metabolism of PrP molecules carrying mutations associated with familial prion diseases [21].
• We report here that mutant PrP molecules are delayed in their maturation to an endoglycosidase H-resistant form after biosynthetic labeling, suggesting that they are impaired in their exit from the endoplasmic reticulum (ER) [21].

Associations of Prnp with chemical compounds

• Also cadmium, but not zinc or manganese, upregulated Prnp promoter activity in PC12 clones [16].
• The prion protein-rich membrane domains contained, as well, about 50% of the sphingolipids, cholesterol and phosphatidylcholine present in the sphingolipid-enriched membrane fraction [17].
• We propose that this unusual beta-turn-rich form of PrP may be a precursor of PrPSc and a candidate for the neurotoxic molecule in prion pathogenesis [22].
• Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems [23].
• In situ hybridization demonstrated that PrP mRNA was localized in and around the fibrous septa of carbon tetrachloride (CCl4)-treated liver [24].

Regulatory relationships of Prnp

• Consistently, zitter rat brains express the normal cellular PrP (PrPC), but do not accumulate the protease-resistant modified isoform (PrPSC) [25].
• Thus, although beta 25-35 and PrP 106-126 robustly activated CPP32, their neurotoxic effect was independent of this caspase activation [26].

Other interactions of Prnp

• Prion protein DRMs contained significantly more unsaturated, longer chain lipids than Thy-1 DRMs and had 5-fold higher levels of hexosylceramide [27].
• Fluorescence microscopy experiments showed that Fyn and Prion protein were mostly not colocalized within a single neuron [20].
• These results indicate that PrP is not involved in the pathogenesis of spongiform encephalopathy in zitter rats [25].
• Astrocytic regulation of NMDA receptor subunit composition modulates the toxicity of prion peptide PrP106-126 [28].
• The selectivity of this effect indicates that PrPSc is directly involved in the clusterin up-regulation seen in prion-related encephalopathies and is associated with astroglial cells [29].

Analytical, diagnostic and therapeutic context of Prnp

• Dot and Northern blot analyses suggest a limited expression of PrP in rat tissues and indicate that PrP expression is decreased in the brain during the acute phase response systemically [30].
• The cellular prion protein patterns in adult mouse and rat brain, and in neuronal cell lines, appeared highly heterogeneous, as distinct levels and glycoforms of cellular prion protein were revealed by immunoblotting of corresponding samples [4].
• Alternatively, chromaffin cells from xenogeneic sources such as bovine adrenal medulla were successful in the experimental treatment of pain, but recent concern over risk of prion transmission precluded use of bovine grafts in human clinical trials [31].
• Using ultrastructural preembedding immunocytochemistry and a monoclonal anti-mouse prion protein antibody, this report shows that cellular prion protein is present in all cortico-cerebellar and deep nuclei neuronal cell types, as well as in all glial cell types [32].
• The same lipids were also present in the low density fraction of a gradient centrifugation of prion-rods after sonication in 0.2% SDS [33].

References