Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice
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Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice. / Puig Martorell, Berta; Altmeppen, Hermann C; Ulbrich, Sarah; Linsenmeier, Luise; Krasemann, Susanne; Chakroun, Karima; Acevedo-Morantes, Claudia Y; Wille, Holger; Tatzelt, Jörg; Glatzel, Markus.
in: SCI REP-UK, Jahrgang 6, 2016, S. 24970.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice
AU - Puig Martorell, Berta
AU - Altmeppen, Hermann C
AU - Ulbrich, Sarah
AU - Linsenmeier, Luise
AU - Krasemann, Susanne
AU - Chakroun, Karima
AU - Acevedo-Morantes, Claudia Y
AU - Wille, Holger
AU - Tatzelt, Jörg
AU - Glatzel, Markus
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1038/srep24970
DO - 10.1038/srep24970
M3 - SCORING: Journal article
C2 - 27117504
VL - 6
SP - 24970
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
ER -