Se presentan de forma sistemática los principales métodos de diagnóstico clínico y de laboratorio de la encefalopatía espongiforme bovina (EEB), enfermedad. encefalopatia espongiforme bovina. Definition from Wiktionary, the free dictionary . Jump to navigation Jump to search. See also: encefalopatía espongiforme. Abstract. LAURINDO, Ellen Elizabeth and BARROS FILHO, Ivan Roque de. Atypical bovine spongiform encephalopathy: a review. Arq. Inst.

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Arch Med Vet 43, Prion biology and bovine spongiform encephalopathy. The complex nature of prions has intrigued the scientific community during the last 70 years.

Since the first indication of scrapie infectivity and the experimental transmission of the scrapie agent inprions and their associated transmissible spongiform encephalopathies TSEs have been under constant investigation. TSEs are neurodegenerative and fatal diseases with no early diagnosis, treatment or cure.

Despite their diverse presentations, all TSEs stem from the infectious, spontaneous or hereditary conversion of the host-encoded cellular prion protein PrP C into the pathogenic isoform PrP Sc. Another enigmatic aspect of the prion biology is the potential physiological function of PrP Ca bovinaa that is widely distributed in mammalian tissues and intensely expressed in the nervous system.

PrP C has been associated to several biological roles including cellular adhesion, protection and differentiation.

The unpredictable properties espkngiforme the PrP Sc and the complex presentation of TSEs have opened many questions yet to be answered. Espongfiorme potential zoonotic transmission of the bovine spongiform encephalopathy BSE has generated intense concern in the international community over animal product biosecurity.

During the last years, research in prion biology has mainly focused on determination of the pathogenesis of TSEs and the development of diagnostic and therapeutic methods. However, further research in prion biology is required in order to understand the complex nature of TSEs and how these diseases can be controlled.

The scientific community has been intrigued with the complex nature of prions for over 70 years. The first indication of prion infectivity was reported in in Scotland after immunization of sheep against louping ill. The vaccines used were accidentally elaborated from brain extracts obtained from sheep infected bovinq scrapie Gordon The fact that eight percent of the immunized animals developed scrapie, with the experimental transmission of the agent performed the same year, demonstrated the infectious capacity of scrapie among sheep and goats Cullie and Chele InHadlow suggested that Kuru, a neurodegenerative disease that affected New Guinea tribes might be similar to scrapie due to similarities in epidemiology, clinical encefalopatiz and pathological findings.

This hypothesis was later confirmed in by the successful transmission of Kuru to chimpanzees after incubation of 18 to 21 months Encefallpatia et al One year later, Alper and colleagues reported that the molecular weight espongiforne the scrapie agent was significantly lower compared to a conventional virus Alper et al Moreover, Apler showed encefalppatia the scrapie agent was able to espobgiforme doses of ultraviolet radiation UV that are sufficient to inactivate nucleic acids.

These experiments led to the formulation of the protein-only hypothesis, which described the scrapie agent as a particle conformed by a proteinaceous structure devoid of nucleic acids with the unique capacity to autoreplicate Griffith In the s, Prusiner reported abundant experimental data in support of this hypothesis and proposed for the first time encsfalopatia term “prion” to describe the scrapie agent. A prion was defined as small proteinaceous infectious particle which was resistant to inactivation by most procedures that modify nucleic acids Prusiner This controversial suggestion supported the idea of a scrapie agent consisting only of an infectious protein and discredited the model that included a small nucleic acid in the core of the protein.

Furthermore, one of the most intriguing aspects of the prion biology was the discovery of a host-encoded cellular prion protein or PrP C Oesch et al This discovery guided to the formulation of the prion hypothesis that postulates that the agent responsible for prion propagation is originated by autocatalytic conversion of PrP C encefalopahia the pathogenic isoform PrP Sc.

Bovine spongiform encephalopathy

The unpredictable properties of PrP Sc and the potential zoonotic transmission of the bovine spongiform encephalopathy BSE have generated intense concern in the international community over animal product biosecurity. The objective of this report is to present an update of the current knowledge on prion biology and to review some of the features of BSE pathophysiology.

However, further research in prion biology will continue to be the foundation for understanding the complex nature of TSEs and how these diseases can be controlled. The structure of PrP C is highly conserved among species and throughout evolution, suggesting an important biological role Gossert et al Before post-translational modification, PrP C is composed of a sequence of amino acids with a slight variation between species depending on the number of octapeptide repeats Prusiner and Scott During protein maturation, PrP C is exposed to several modifications in the rough endoplasmic reticulum ER including replacement of the peptide signal located between amino acids with a glycophosphatidylinositol GPI anchor.


Additionally, two asparagines at amino acids are glycosylated and one disulfide bridge is added between two cysteine residues PrusinerHarris The mature protein is divided in two distinct regions: PrP C is found as a mixture of these forms with variable proportions depending on the tissue and animal species Russelakis-Carneiro et al The expression of PrP C is high in the central nervous system; however, recent reports have showed a wide expression in various somatic tissues including thymus, intestine, heart, kidney and skin Peralta and Eyestone The usual cellular location of PrP C is attached by the GPI anchor to membrane domains rich in cholesterol and sphingolipids known as lipid raft Martins et alDeMarco and Daggett However, part of the pool of PrP C can be internalized via clathrin-mediated endocytosis and accumulate inside the Golgi apparatus.

Furthermore, some of the internalized protein is recycled to the cytoplasmatic membrane by kinesin anterograde transport Hachiya et al Although the specific location for PrP Sc conversion has not yet been determined, it is believed that formation of PrP Sc occurs at the exterior face of the plasma membrane Jeffrey et al Endocytosis of PrP Sc may occur mediated by ubiquitin and clathrin molecules into lysosomes for degradation Jeffrey et al The prion gene PRNP has homologues in all vertebrates with conserved regions between mammals and birds Premzl and Gamulin Bovine, sheep, mouse and rat PRNP possess three exons with the protein coding sequence located entirely within the third exon figure 1 Oesch et alInoue et al Using chloramphenicol acetyltransferase CAT plasmids, the promoter region of the bovine gene was detected in the region between and relative to the transcription start site, similar to the rat promoter region Inoue et al Several regulatory regions including the promoter has been identified in the bovine PRNP with the major region of transcriptional control located upstream of the initiation site.

Several variables have been reported to influence PRNP expression under in vitro conditions including nerve growth factor NGFrate of prion infection and epigenetic changes Bueler et alMartins et al The PRNP gene size is approximate 21 kb. After transcription and splicing, the mRNA molecule is formed by exons 1, 2 and 3.

Exon 3 carries the coding sequence that encodes the PrP C protein after translation. Despite intense investigation during recent years, the function of PrP C remains enigmatic. Some studies have suggested a cellular protective role of PrP C against oxidative stress. Experiments have showed that neurons from PRNP knockout mice and cultured in vitro displayed higher susceptibility to oxidative agents such as hydrogen peroxide, xanthine oxidase and copper ions compared to wild-type neurons Brown et al Moreover, brain tissue collected from PRNP knockout mice exhibited biochemical changes including increased levels of protein carbonyls and lipid peroxidation products, which are indicative of oxidative damage Wong et al Several lines of evidence have proposed a cytoprotective role of PrP C against internal or environmental stresses that initiate apoptosis.

This anti-apoptotic potential is primarily based on the capacity of PrP C to inhibit the action of the pro-apoptotic protein Bax Bounhar et al Alternatively, PrP C may act upstream of Bax, affecting the activity of BH3, Bcl-2 or Bcl-X Lor downstream, suppressing the effects of Bax in the release of cytochrome c or activation of Apaf-1 and caspases Roucou et alWestergard et al Other studies have reported a close similarity between the homologous domain of the anti-apoptotic protein Bcl-2 and the PrP C octapeptide region.

This analogy in the protein structure may allow PrP C to mimic Bcl-2 function and induce cell survival Roucou et alWestergard et al In addition to the cytoprotective role, PrP C has been also implicated as a cell proliferation and differentiation factor.

Recently it was reported that PrP C -null mice exhibited an impaired capacity of self-renewal of hematopoietic stem cell populations after serial transplantation in the bone marrow Zhang et al The potential mitogenic capacity has also been supported by studies showing a decrease in T lymphocyte proliferation in mice devoid of PrP C Bainbridge and Walker The role of PrP C in differentiation was suggested by high levels of expression in cells that ceased proliferation and became differentiated into neurons during early stages of mice embryogenesis Tremblay et al Recently, it has been reported that PrP C displayed a positive effect in the proliferation of neural precursor cells and showed a positive correlation with neuronal differentiation Steele et alPeralta et al The capacity of PrP C to bind to several different molecules has opened the idea that this protein may exert its function in association with a ligand.

The location of PrP C in the extracytoplasmic face of the lipid bilayer restricts the interaction to transmembrane and secreted proteins. Transmembrane variants of PrP C could potentially interact with cytoplasmic partners; however, these forms are normally present in low amounts in the absence of predisposing mutations in the PrP C molecule Stewart and Harris The membrane association and the interaction with ligands suggest the hypothesis that PrP C may activate transmembrane signaling processes associated to neuronal survival, differentiation and neurite outgrowth.

Neuronal growth has also been observed during PrP C interaction with the neuron espongiofrme adhesion protein N-CAM after its recruitment from lipid rafts and the espongiofrme of Fyn kinase Santuccione et al In addition, studies have showed that PrP C binds the receptor of laminin in neural cells resulting in dendritic extension, neuronal migration, axonomic regeneration and suppression of cell death induced by kainic acid injection Martins et al The prion hypothesis or protein-only hypothesis postulates that the agent responsible for prion propagation is originated by autocatalytic conversion of PrP C into the pathogenic isoform Griffith Conversion into Espobgiforme Sc involves a drastic alteration in the protein configuration as well as in its biochemical properties.


Therefore, the newly formed PrP Sc structure is highly planar and stable showing strong resistance to temperature, pH, disinfectants and enzymatic degradation Espongiforne Additional supporting evidence of the prion hypothesis has been originated from studies that reported resistance to prion infection in mice lacking the PRNP gene Bueler et al These knockout models not only evidenced the requirement of a host-encoded PrP C protein for the infection process but also allowed a better understanding of the pathogenesis of TSEs.

However, the most compelling evidence to probe this theory is yet to be reported. Some researchers claimed that a confirmatory experiment will consist in the in vitro conversion of PrP C molecules into a pathogenic isoform with the capacity to induce TSE infection Chesebro Mutations induced to recombinant PrP C have resulted in destabilization of the protein configuration and formation of a PrP Sc -like molecule; however, this mutated agent was unable to induce prion disease Chiesa et alBocharova et al It is possible that additional factors including a transitional form of PrP and host-derived proteins or non-protein compounds chaperones, glycosaminoglycans or short nucleic acids are required to sustain in vitro generation of PrP Sc Castilla et alAguzzi et al Moreover, mice co-expressing both human and mice PrP were resistant to prion replication as consequence of the interaction of mice PrP C with an additional factor termed protein X that inhibited human PrP C conversion Telling et al Recent studies reported the in vitro generation of PrP Sc molecules using a protein misfolding cyclic amplification technique PMCA that allows the repetitive amplification of the misfolding event Castilla et al Although, the newly formed PrP Sc generated by this technique was able to infect wild-type Syrian hamsters, the use of crude brain homogenates to amplificate these molecules may have also resulted in the addition of different components responsible for the infection.

Further simplification of PMCA has been reported by substituting shaking for sonication as described for the quaking-induced conversion QuIC reactions Atarashi et al The QuIC assay can detect within one day less than one lethal intracerebral dose sub-femtogram amount of PrP Sc in hamster brain homogenates.

Both isoforms have important differences in secondary protein configuration. Two distinct models have been proposed to explain the autocatalytic conversion of PrP C espongigorme, a process not mediated by nucleic acids that challenge the central dogma of molecular biology. The template-assisted model postulates a thermodynamically stable conversion between both PrP isoforms figure 3.

Biología del prion y encefalopatía espongiforme bovina

The process is catalyzed by a yet unidentified protein X that has chaperone-like properties and facilitates aggregation of both isoforms Cohen and Prusiner Protein X promotes PrP C conversion by binding a discontinuous epitope in the globular C terminal region of the protein Kaneko et al A second model termed nucleation-polymerization proposes a similar thermodynamic equilibrium between both isoforms figure 3.

However, after PrP C conversion, the model describes a highly unstable and transient PrP Sc molecule that would be stabilized only by forming ordered aggregates.

The stabilized oligomers act as nuclei to recruit monomeric PrP Sc in a process that displaces the thermodynamic equilibrium and accelerates PrP Sc formation CaugheyCaughey and Lansburry Despite a bulk of evidence in support of the prion hypothesis, alternative models suggesting the participation of viral particles, virinos and small RNAs have also been proposed.

Co-sedimentation of retroviral RNA with PrP Scand purification of short RNA fragments from infectious fractions suggest the participation of nucleic acids as part of the infectious particle Akowitz et al The virino model describes the TSE agent as a proteinaceous structure containing nucleic acids with a virus-like conformation Chesebro The finding that prions have a variety of strains that correlates with a species-specific symptomology and histopathology in TSEs has also been used as evidence to support the virino model Chesebro However, the strain phenomenon can be explained by the variation in PrP Sc protein secondary structure and not necessarily by the existence of viral strains containing nucleic acids Prusiner The template assisted model includes the participation of a conversion factor that mediates PrP transformation.

The nucleation-polymerization model describes a PrP Sc heterodimer intermediate complex that induces aggregation and conversion of the molecule. The pathogenesis of TSEs including the mechanism of neuronal degeneration has not been completely elucidated.

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