Reduced Translocation of Nascent Prion Protein During ER Stress Contributes to Neurodegeneration

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2008 Sep 23

PMID 18804434

Citations 69

Authors

Neena S Rane

Sang-Wook Kang

Oishee Chakrabarti

Lionel Feigenbaum

Ramanujan S Hegde

Affiliations

Soon will be listed here.

Abstract

During acute stress in the endoplasmic reticulum (ER), mammalian prion protein (PrP) is temporarily prevented from translocation into the ER and instead routed directly for cytosolic degradation. This "pre-emptive" quality control (pQC) system benefits cells by minimizing PrP aggregation in the secretory pathway during ER stress. However, the potential toxicity of cytosolic PrP raised the possibility that persistent pQC of PrP contributes to neurodegeneration in prion diseases. Here, we find evidence of ER stress and decreased translocation of nascent PrP during prion infection. Transgenic mice expressing a PrP variant with reduced translocation at levels expected during ER stress was sufficient to cause several mild age-dependent clinical and histological manifestations of PrP-mediated neurodegeneration. Thus, an ordinarily adaptive quality-control pathway can be contextually detrimental over long time periods. We propose that one mechanism of prion-mediated neurodegeneration involves an indirect ER stress-dependent effect on nascent PrP biosynthesis and metabolism.

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