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

Holger Wille,Sarah Ulbrich,Karima Chakroun,Claudia Y Acevedo-Morantes,Hermann C Altmeppen,Jörg Tatzelt,Markus Glatzel,Berta Puig,Susanne Krasemann,Luise Linsenmeier

doi:10.1038/srep24970

Abstract

Misfolding of proteins in the biosynthetic pathway in neurons may cause disturbed protein homeostasis and neurodegeneration. The prion protein (PrPC) is a GPI-anchored protein that resides at the plasma membrane and may be misfolded to PrPSc leading to prion diseases. We show that a deletion in the C-terminal domain of PrPC (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 PrPC. 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.

Highlights

IntroductionOverload of misfolded proteins challenges the endoplasmic reticulum (ER) capacity, leading to ER stress and induction of the unfolded protein response (UPR) to restore homeostasis (reviewed in[4,5])
Cells transfected with PrPΔ 214–229 expressed a main band at around 29 kDa when assessed by Western blot (Fig. 1b) in a proportion about ~60% of the amount of wild-type PrPC (WTPrPC)
We define a novel neurodegenerative pathway associated with defective intracellular PrP trafficking that may be relevant in prion diseases and other neurodegenerative protein misfolding disorders

Summary

Introduction

Overload of misfolded proteins challenges the ER capacity, leading to ER stress and induction of the unfolded protein response (UPR) to restore homeostasis (reviewed in[4,5]) When this stress becomes chronic, it results in cell death. The prion protein (PrPC), a glycosylphosphatidylinositol (GPI)-anchored membrane protein targeted to detergent resistant membranes (DRMs)[9], plays fundamental roles in prion diseases, a group of fatal neurodegenerative disorders[10,11,12]. In humans, they can be sporadic (e.g. sporadic Creutzfeldt-Jakob disease (sCJD)), genetic (e.g. Gerstman-Sträussler-Scheinker syndrome (GSS) or Fatal Familial Insomnia (FFI)) or acquired (iatrogenic CJD (iCJD) or new variant CJD (vCJD)). Note that PrPΔ 214–229 is found in the IP fraction, indicating GPIanchoring

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