RESUMO
The cleavage of amyloid precursor protein (APP) by caspases unmasks a domain extending from membrane to caspase cleavage site. This domain induces apoptosis in vitro and in vivo when overexpressed in neurons through the help of an internalization vector. In this model, we previously showed that SET rapidly binds to the internalized domain and is involved in downstream deleterious effects. Under these conditions SET mislocalizes from the nucleus to the cytoplasm, as in Alzheimer's disease (AD). In this report using the same model, we show that PAT1 attaches to the internalized domain earlier than SET and that this binding causes an increase in the levels of APP and APLP2 at the cell surface. Down regulation experiments of PAT1 and of APP and APLP2 show that the increase of the levels of APP and APLP2 at the cell surface triggers the cell death signal and SET mislocalization into the cytoplasm. In the context of AD these data suggest that mislocalization of SET into the cytoplasm may occur downstream of first cell death signal events involving PAT1 protein.
Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Membrana Celular/metabolismo , Citoplasma/metabolismo , Chaperonas de Histonas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Simportadores/metabolismo , Fatores de Transcrição/metabolismo , Sistemas de Transporte de Aminoácidos/química , Sistemas de Transporte de Aminoácidos/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Apoptose/fisiologia , Biotinilação/métodos , Caspases/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Proteínas de Ligação a DNA , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Embrião de Mamíferos , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Estrutura Terciária de Proteína/genética , Estrutura Terciária de Proteína/fisiologia , Transporte Proteico/fisiologia , RNA Interferente Pequeno/farmacologia , Simportadores/química , Simportadores/genéticaRESUMO
Although susceptibility to scrapie is largely controlled by the PrP gene, the role of other genes that affect scrapie resistance in sheep is now confirmed. Following the detection of quantitative trait loci (QTL) on chromosomes 6 and 18 in a half-sib family with an ARQ/VRQ susceptible PrP genotype, the whole pedigree of a naturally infected flock was investigated to confirm these QTL regions in different PrP genotypes. The present study has allowed us to confirm the QTL on chromosome 18, and to demonstrate the QTL effects in several PrP genotypes.
