Endoplasmic reticulum stress, PrP trafficking, and neurodegeneration

Abstract

In this issue of Developmental Cell, Rane et al. report a cellular pathway to link PrP(Sc), via ER stress and the activation of a preemptive quality control process, to neurodegeneration in a PrP-dependent manner. This pathway puts together several pieces in the puzzle of the relationship between PrP(Sc) and brain damage and may in part explain the mechanism of prion neurodegeneration.

Figure 1. Role of PrP^Sc and Mechanism of Neurodegeneration

Although PrP^Sc is certainly associated to the pathogenesis of TSEs, its role is neurodegeneration is controversial. Several observations suggest that PrP^Sc levels do not correlate with the extent of brain damage and that the natively folded PrP^C is required for neurodegeneration. Three non-mutually exclusive models can be proposed to explain the discrepancies and the implication of PrP^C. (A) First, the infectious and neurotoxic PrP species might not be the same. Indeed, it is possible that an undetectable misfolded intermediate might be responsible for neurotoxicity in a way similar to that proposed for other neurodegenerative diseases. The transient nature of these intermediates determines that its presence depends on the permanent synthesis of new PrP^C. (B) PrP^C located in the cell surface may act as a receptor for PrP^Sc, triggering a signal transduction pathway leading to neurodegeneration. (C) As proposed by Rane and colleagues in this issue (Rane et al., 2008), induction of ER stress by PrP^Sc may lead to translocation of nascent PrP^C molecules to the cytosol for proteasomal degradation as a way to alleviate the damaged ER (pQC pathway). However, this mechanism of defense turns negative under chronic ER stress conditions, overwhelming the proteasome and leading to the cytosolic accumulation of potentially toxic PrP molecules.