Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice.
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.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Berta
B
Puig
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Hermann C
HC
Altmeppen
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry und Pathobiochemistry, Ruhr University Bochum, Bochum 44801, Germany.
Sarah
S
Ulbrich
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Luise
L
Linsenmeier
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Susanne
S
Krasemann
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Karima
K
Chakroun
Centre for Prions and Protein Folding Diseases and Department of Biochemistry, University of Alberta, Edmonton, T6G 2M8 Alberta, Canada.
Claudia Y
CY
Acevedo-Morantes
Centre for Prions and Protein Folding Diseases and Department of Biochemistry, University of Alberta, Edmonton, T6G 2M8 Alberta, Canada.
Holger
H
Wille
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry und Pathobiochemistry, Ruhr University Bochum, Bochum 44801, Germany.
Jörg
J
Tatzelt
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Markus
M
Glatzel
D000818:Animals; D002531:Cerebellum / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000503:physiopathology*; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism*; D055571:Secretory Pathway; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D050505:Mutant Proteins; D000072002:Prion Proteins; D048051:p38 Mitogen-Activated Protein Kinases