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Presynaptic differentiation takes place over three interrelated acts involving the biogenesis and trafficking of molecular complexes of active zone material, the "trapping" or stabilization of active zone sites, and the subsequent development of mature synapses. Although the identities of proteins involved with establishing presynaptic specializations have been increasingly delineated, the exact functional mechanisms by which the active zone is assembled remain poorly understood. Here, we discuss a theoretical model for how the trapping stage of presynaptic differentiation might occur in developing neurons. We suggest that subsets of active zone proteins containing polyglutamine domains undergo concentration-dependent prion-like conversions as they accumulate at the plasma membrane. This conversion might serve to aggregate the proteins into a singular structure, which is then able to recruit scaffolding agents necessary for regulated synaptic transmission. A brief informatics analysis in support of this 'Q' assembly hypothesis--across commonly used models of synaptogenesis--is presented.

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Prion diseases are transmissible spongiform encephalopathies (TSEs), attributed to conformational conversion of the cellular prion protein (PrP(C)) into an abnormal conformer that accumulates in the brain. Understanding the pathogenesis of TSEs requires the identification of functional properties of PrP(C). Here we examine the physiological functions of PrP(C) at the systemic, cellular, and molecular level. Current data show that both the expression and the engagement of PrP(C) with a variety of ligands modulate the following: 1) functions of the nervous and immune systems, including memory and inflammatory reactions; 2) cell proliferation, differentiation, and sensitivity to programmed cell death both in the nervous and immune systems, as well as in various cell lines; 3) the activity of numerous signal transduction pathways, including cAMP/protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, as well as soluble non-receptor tyrosine kinases; and 4) trafficking of PrP(C) both laterally among distinct plasma membrane domains, and along endocytic pathways, on top of continuous, rapid recycling. A unified view of these functional properties indicates that the prion protein is a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences upon both physiology and behavior.

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The cellular prion protein (PrPc) is a protein found on the cell surface of many cell subtypes, especially neurons, anchored by a glycosyl-phosphatidylinositol residue. The physiological role of PrPc is still not understood. However, it is known that participates in copper uptake, protection against oxidative stress, cell adhesion, differentiation, signalling and cell survival. Moreover, it is also involved in memory formation. Despite the numerous functions given to PrPc, its discovery did not occur due to its altered isoform involvement (PrPsc) as an infectious agent of spongiform encephalopathies These diseases are unique because they can be hereditary, sporadic or have an acquired etiology. Much has been done concerning this intriguing protein, but there is still the need for more studies to truly understand PrPc functions and PrPsc pathogenesis mechanisms. In this way, new and more effective therapeutical approaches can be developed, and more information on other amyloid diseases can be gathered.

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Prion diseases are rare neurodegenerative diseases of humans and animals with a lethal evolution. Animal prion infections, such as chronic wasting disease (CWD) and scrapie (sheep) have shown a pattern of horizontal transmission. CWD is an endemic disease that has been affecting thousands of domestic and wild cervids in US for the last three decades. The mode of contamination is not known, although direct contact between infected and non-infected animals via saliva, urine and feces have been considered. Increasing spread of CWD has raised concerns about the potential transmission to humans and the conversion of human prion protein by CWD-associated prions has been demonstrated in laboratory experiments. Fly larvae exposed to brain infected material were able to readily transmit scrapie to hamsters. Prion rods were identified in both larvae and fly pupae. New lines of evidence confirmed that adult flies are also able to express prion proteins. The most prevalent species of myiasis in cattle, sheep and wild cervids (Hypoderma spp.) present a very different life cycle from human myiasis, with a long contact with neurologic structures, such as the spinal canal and epidural fat, that are potentially rich in prion rods. Considering the huge amount of fly larvae that affects each animal, it is important to discuss the possibility that these ectoparasites could theoretically act as reservoirs and vectors for CWD and other prion diseases. It is critical to recognize all the possible factors involved in CWD transmission since ectoparasites could be handled in an easier way than the environmental persistence of infectious prions.

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O prion celular (PrPc) exerce papel fundamental nas encefalopatias espongiformes. No entanto, suas funções fisiológicas ainda não foram totalmente compreendidas. Nosso grupo mostrou, previamente, que PrPc se liga a laminina (LN}, uma proteína da matriz extracelular, e que esta interação medeia adesão neuronal, formação e manutenção de neuritos (GRANER et ai. 2000a). Sabendo-se que a matriz extracelular e em particular, LN, pode influenciar os processos tumorais e metastáticos, decidimos investigar a possível participação de PrPc nestes eventos. Para tanto, células embrionárias mesenquimais (CEM) de camundongos tipo selvagem (Prnp+1 +) ou deficientes do gene de PrPc (Prnp010) foram transfectadas com um vetor que codifica a expressão dos oncogenes rase myc. Foram selecionados três clones transformados a partir de cada grupo de células: CEM Prnp+J+ raslmyc e Prnp010 ras/myc, que possuíam expressão similar de ambas as oncoproteínas. Os clones Prnp+l+ ras/myc e Prnp010 ras/myc apresentaram tempos de duplicação semelhantes in vitro, assim como exibiram doses tumorais mínimas semelhantes quando injetados por via subcutânea no dorso de camundongos tipo selvagem. Os clones Prnp+l+ ras/myc e Prnp010 ras/myc foram testados em modelo de metástase experimental (colonização pulmonar), injetando-se células na veia lateral da cauda de camundongos tipo selvagem. Após 21 dias, o número de colônias pulmonares presentes na superfície pleural foram quantificados. Os clones Prnp010 raslmyc produziram um número de colônias pulmonares estatisticamente superior ao dos clones Prnp +I+ raslmyc. Ensaios de esteróides multicelulares mostraram que os clones Prnp010 ras/myc apresentam uma maior adesão célula-célula do que aqueles Prnp+l+ raslmyc. Entretanto, nenhuma alteração na expressão de ICAM-1 (CD54) ou caderinas foi encontrada entre eles. Por outro lado, experimentos de imunofluorescência, mostraram que células dos clones Prnp010 raslmyc assim como sua parenta! CEM Prnp010 apresentam a integrina avf33 funcionalmente mais ativada do que seus equivalentes Prnp+1 +. Estes dados sugerem que a ausência de PrPc leva a uma regulação positiva na atividade de avf33 integrina. Por sua vez, sabe-se que o aumento da atividade desta integrina pode ser responsável pela maior adesão das células tumorais a vitronectina e componentes sanguíneos como as plaquetas, com conseqüente aumento na formação de êmbolos. Desta forma, variações na expressão de PrPc podem contribuir na sinalização celular, em particular naquela envolvida com a ativação da integrina avf33, que por sua vez participa na formação de êmbolos e conseqüente aumento na colonização de células tumorais (AU)

The cellular prion (PrPc) has a criticai role in spongiform encephalopathies. However, its physiological functions are not completely understood. We have reviously shown that PrPc binds the extracellular matrix protein, laminin (LN), and this interaction affects neuronal cell adhesion, neurite formation and maintenance (GRANER et ai. 2000a). The extracellular matrix and in particular, LN, can affect the tumoral and metastatic processes, therefore we decided to investigate a possible participation of PrPc in such processes. Thus, mesenchimal embryonic cells from wild-type (Prnp+1 +) or PrPc gene ablated mice (Prnp010) were transfected with a vector containing the expression sequences of ras and myc oncogenes. We isolated three transformed clones from each genotype (Prnp+l+ and Prnp010) with similar expression of both oncoproteins. Prnp+r+raslmyc or Prnp010ras/myc clones presented the same doubling time in vitro as well as similar minimum tumoral doses when injected subcutaneously in the dorsal region of wild type mice. In lung colonization assays, an experimental model of metastasis, Prnp+1 +ras/myc or Prnp010raslmyc clones were injected in the lateral tail vein of wild-type mice and the number of pulmonary colonies were counted after 21 days. Prnp010ras/myc clones exhibited a significant higher number of lung colonies than those presented by Prnp+1 +raslmyc ones. Multicellular spheroids from Prnp010ras/myc clones showed a higher cell-cell interaction and a lower cellular scattering when compared with the Prnp +I+ raslmyc ones.However, alterations in the expression of ICAM-1 (CD54) and cadherins were not found between the Prnp010ras/myc and Prnp+1 +raslmyc clones. On the other hand, immunofluoresce assays revealed that Prnp010 ras/myc clones and the mesenchimal embryonic Prnp010 parenta! cells presented a higher avf33 activity when compared to the Prnp +I+ ones. These data suggest that the PrPc depletion leads to a positive regulation of avJ33 integrin activity. lt is well known that tumoral cell adhesion mediated by avJ33, can mediate tumoral cell adhesion to vitronectin and other blood components, such platelets, increasing embolization capacity. Thus, alterations on PrPc expression can regulate cellular signaling, particularly, that involved in av~3 integrin activation which participates on cellular embolization and consequently elevation on pulmonar colonization (AU)

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Cellular prion protein (PrPc) has been associated with some physiological functions in recent reports. Here we investigate behavioral parameters in 3- and 9-month-old mice lacking PrPc protein (Prnp0/0) and in rats after intrahippocampal administration of affinity purified anti-PrPc IgG (0.09 microg/side). No differences were observed between 3-month-old animals. However, 9-month-old Prnp0/0 mice and rats infused with anti-PrPc antibody showed a clear impairment of short- and long-term memory retention of a step-down inhibitory avoidance task. A decreased locomotor activity during exploration of an open field was also observed. These results suggest that systems involved in memory formation become more susceptible to mechanisms that require PrPc between the ages of 3 and 9 months in both mice and rats.

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The role of Gln3p, Nil1p, Dal80p and Ure2p in the nitrogen regulation of ASP3, which codes for the periplasmic Saccharomyces cerevisiae asparaginase II, was investigated. Analysis of enzyme levels and mRNA(ASP3) in two wild-type strains and gln3, nil1, gln3nil1, gln3ure2, nil1ure2, nil1dal80, ure2, dal80 and ure2dal80 mutant cells allowed the study of the qualitative and quantitative regulatory role of the GATA factors and Ure2p on ASP3 expression. The simultaneous presence of Gln3p and Nil1p is a required condition for full gene transcription. Enzyme activity doubled upon nitrogen starvation of either ammonium-grown (possibly due to Nil2p/Deh1p derepression) or proline-grown (due to Dal80p derepression) cells. The ure2 mutation increased enzyme levels five-fold in fresh ammonium-grown cells and ten-fold in fresh proline-grown cells. The combined effects of the ure2 mutation and nitrogen starvation on ammonium- or proline-grown cells resulted in an overall 10-20-fold enzyme activity increase, respectively, in comparison with the wild-type cells.

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El objetivo de esta comunicación es actualizar y transmitir información sobre medidas de prevención y bioseguridad de estos agentes infecciosos no convencionales. Los priones están constituidos por protínas modificadas de la (Pr PC) normal en (PrPsc) scrapie por un mecanismo de autorreplicación sin la intervención de DNA o RNA, siendo esto un enigma científico de años de controversias. Las enfermedades priónicas son de prevalencia en los cinco continentes, la transmisión interhumana fue comprobada experimentalmente por vía bucal. Estos agentes infecciosos no convencionales son resistentes a procedimientos habituales de desinfección y esterilización. Como eficaz para su inactivación se menciona el calor húmedo, autoclave de prevacío a 134-38 grados C durante 18 minutos de meseta. La inmersión durante 1 hora en hipoclorito de Na al 2 por ciento (20.000 ppm) reduce pero no elimina su transmisibilidad. Futuros avances de la biología molecular y de la patogénesis de dichas enfermedades optimizarán su inactivación y prevención (AU)

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Prions are the etiological agents for infectious degenerative encephalopaties acting by inducing conformational changes in the cellular prion protein (PrPc), which is a cell membrane GPI anchored glycoprotein. Besides its conservation among species and expression in most tissues, and in particular, in high levels in the nervous system, the role for cellular prion protein remained obscure for some time. Initial skepticism about such a role was mainly due to the absence of a gross phenotype alteration in cellular prion protein null mice. In the last few years, some possible biological functions for cellular prion protein have been described. Copper binds to the molecule and the resulting complex may be responsible for cell protection against oxidative stress. Cellular prion protein is also a high-affinity ligand for laminin, and induces neuronal cell adhesion, neurite extension and maintenance. The binding site resides in a carboxy-terminal peptide of the gamma-1 chain, which is very conserved among all laminin types, indicating that this interaction may be relevant in other tissues besides the brain. Moreover, cellular prion protein association with a peptide that mimics a putative ligand at the cell surface, p66, triggers neuroprotective signals through a cAMP/PKA-dependent pathway. Since PrPc recycles from membrane to an intracellular compartment, which is induced by copper binding, it is also possible that the internalization mechanism allows switching off elicited signals.

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Prions, the etiological agents for infectious degenerative encephalopathies, act by inducing structural modifications in the cellular prion protein (PrPc). Recently, we demonstrated that PrPc binds laminin (LN) and that this interaction is important for the neuritogenesis of cultured hippocampal neurons. Here we have used the PC-12 cell model to explore the biological role of LN-PrPc interaction. Antibodies against PrPc inhibit cell adhesion to LN-coated culture plaques. Furthermore, chromophore-assisted laser inactivation of cell surface PrPc perturbs LN-induced differentiation and promotes retraction of mature neurites. These results point out to the importance of PrPc as a cell surface ligand for LN.

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Hace dos décadas Stanley Prusiner un neurólogo norteaméricano propuso un nuevo tipo de agentes infecciosos que denominó Priones. Estos nuevos patógenos consiten principalmente en proteína y carecen de ácido nucleico. Muchas enfermedades neurodegenerativas conocidas como encefalopatías espóngiformes tales como la enfermedad de Creutzfeld-Jakob, pueden ser explicadas a través de estas novedosas partículas. En esta revisión se explican algunos aspectos históricos, biológicos y clínicos de los priones

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The word "prion" was created in 1982 to name the etiological agent of the transmissible spongiform encephalopathies (TSE), a group of degenerative diseases affecting central nervous system of man and animals, including bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD). Prions present two isoforms: PrPC, cellular or normal, which exists in all vertebrates and is sensitive to detergents and proteases, and PrPSc, disease associated, partially resistant. The molecular weight of both PrPC and PrPSc is 30-35 kD; after treatment with detergents and proteases PrPSc originates PrP27-30 (27-30 kD). PrPC is also denominated PrPsens, and PrPSc is PrPres. PrPSc and PrP27-30 cause disease. PrPC presents polymorphisms specifically associated with some TSE. The "prion hypothesis" says that PrPSc transmits its characteristic resistance to PrPC through conformational changes, and accumulation of the protein, without involvement of nucleic acids, causes disease. Most of the hypothesis has been demonstrated with transgenic mice, computer models and recombinant proteins, but the existence of strains of the TSE agents has not been explained. The description of similar mechanisms of propagation of protein conformational properties in Saccharomyces cereviseae has extended the meaning of the prion definition. Although the transmission of conformational changes between PrPC and PrPSc was experimentally shown, the pathogenesis of the TSE remains unknown. The relationship between BSE and vCJD is mentioned.(AU)

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The word "prion" was created in 1982 to name the etiological agent of the transmissible spongiform encephalopathies (TSE), a group of degenerative diseases affecting central nervous system of man and animals, including bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD). Prions present two isoforms: PrPC, cellular or normal, which exists in all vertebrates and is sensitive to detergents and proteases, and PrPSc, disease associated, partially resistant. The molecular weight of both PrPC and PrPSc is 30-35 kD; after treatment with detergents and proteases PrPSc originates PrP27-30 (27-30 kD). PrPC is also denominated PrPsens, and PrPSc is PrPres. PrPSc and PrP27-30 cause disease. PrPC presents polymorphisms specifically associated with some TSE. The "prion hypothesis" says that PrPSc transmits its characteristic resistance to PrPC through conformational changes, and accumulation of the protein, without involvement of nucleic acids, causes disease. Most of the hypothesis has been demonstrated with transgenic mice, computer models and recombinant proteins, but the existence of strains of the TSE agents has not been explained. The description of similar mechanisms of propagation of protein conformational properties in Saccharomyces cereviseae has extended the meaning of the prion definition. Although the transmission of conformational changes between PrPC and PrPSc was experimentally shown, the pathogenesis of the TSE remains unknown. The relationship between BSE and vCJD is mentioned.

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