Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice.
Sci Rep
; 6: 24970, 2016 04 27.
Article
em En
| MEDLINE
| ID: mdl-27117504
ABSTRACT
Misfolding of proteins in the biosynthetic pathway in neurons may cause disturbed protein homeostasis and neurodegeneration. The prion protein (PrP(C)) is a GPI-anchored protein that resides at the plasma membrane and may be misfolded to PrP(Sc) leading to prion diseases. We show that a deletion in the C-terminal domain of PrP(C) (PrPΔ214-229) leads to partial retention in the secretory pathway causing a fatal neurodegenerative disease in mice that is partially rescued by co-expression of PrP(C). Transgenic (Tg(PrPΔ214-229)) mice show extensive neuronal loss in hippocampus and cerebellum and activation of p38-MAPK. In cell culture under stress conditions, PrPΔ214-229 accumulates in the Golgi apparatus possibly representing transit to the Rapid ER Stress-induced ExporT (RESET) pathway together with p38-MAPK activation. Here we describe a novel pathway linking retention of a GPI-anchored protein in the early secretory pathway to p38-MAPK activation and a neurodegenerative phenotype in transgenic mice.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Priônicas
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Proteínas Quinases p38 Ativadas por Mitógeno
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Via Secretória
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Proteínas Priônicas
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Alemanha