Send to

Choose Destination
Sci Rep. 2016 Apr 27;6:24970. doi: 10.1038/srep24970.

Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice.

Author information

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry und Pathobiochemistry, Ruhr University Bochum, Bochum 44801, Germany.
Centre for Prions and Protein Folding Diseases and Department of Biochemistry, University of Alberta, Edmonton, T6G 2M8 Alberta, Canada.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center