RESUMO
The prion protein (PrP) is central to the aetiology of the prion diseases, transmissible neurodegenerative conditions of humans and animals. PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor-mediated fast inhibition and impaired long-term potentiation in the hippocampus. 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. The ability of human PrP to compensate for loss of murine PrP will allow direct study of the functional consequences of the 18 human PrP mutations, which cause the inherited prion diseases; this phenotype can now form the basis of the first functional assay for PrP.
Assuntos
Camundongos Transgênicos/genética , Camundongos Transgênicos/fisiologia , Príons/genética , Animais , Sequência de Bases , Humanos , Masculino , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Neurofisiologia , Fenótipo , Doenças Priônicas/genéticaRESUMO
Strains of transmissible spongiform encephalopathies are distinguished by differing physicochemical properties of PrPSc, the disease-related isoform of prion protein, which can be maintained on transmission to transgenic mice. 'New variant' Creutzfeldt-Jakob disease (CJD) has strain characteristics distinct from other types of CJD and which resemble those of BSE transmitted to mice, domestic cat and macaque, consistent with BSE being the source of this new disease. Strain characteristics revealed here suggest that the prion protein may itself encode disease phenotype.
Assuntos
Síndrome de Creutzfeldt-Jakob/etiologia , Príons/genética , Animais , Gatos , Síndrome de Creutzfeldt-Jakob/classificação , Síndrome de Creutzfeldt-Jakob/transmissão , Encefalopatia Espongiforme Bovina/etiologia , Endopeptidase K/metabolismo , Variação Genética , Glicosilação , Hormônio do Crescimento/administração & dosagem , Humanos , Macaca , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas PrPC/química , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Proteínas PrPSc/química , Proteínas PrPSc/genética , Proteínas PrPSc/metabolismo , Príons/química , Príons/classificação , Príons/metabolismo , Conformação ProteicaRESUMO
Prion diseases are transmissible neurodegenerative conditions of humans and animals. Prions consist principally of a post-translationally modified form of prion protein (PrP), PrP(Sc), which is partly protease resistant. Transmission of prion diseases between species is limited by a 'species barrier' determined in part by the degree of sequence homology between host PrP and inoculated PrP(Sc) (ref.3) and by prion strain type. The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom and other countries has led to concerns that transmission to humans may occur by dietary exposure. BSE appears to be caused by a single strain, distinct from those of natural or experimental scrapie, which is also seen in the new prion diseases of cats and ruminants that have presumably arisen from dietary BSE exposure. Here we show that transgenic mice expressing human PrP in addition to mouse PrP can generate human PrP(Sc) and 'human' prions. These mice therefore provide a model to study experimentally the species barrier limiting BSE transmission to humans. Incubation periods to BSE in transgenic mice are not shortened by expression of human PrP, and only mouse PrP(Sc) is produced in response to such challenge.