Elsevier

Brain Research Reviews

Volume 38, Issue 3, February 2002, Pages 328-339
Brain Research Reviews

Review
Oxidative stress and the prion protein in transmissible spongiform encephalopathies

https://doi.org/10.1016/S0165-0173(01)00150-3Get rights and content

Abstract

Transmissible spongiform encephalopathies form a group of fatal neurodegenerative disorders that have the unique property of being infectious, sporadic or genetic in origin. These diseases are believed to be the consequence of the conformational conversion of the prion protein into an abnormal isoform. Their exact pathogenic mechanism remains uncertain, but it is believed that oxidative stress plays a central role. In this article, we will first review in detail the data supporting the latter hypothesis. Subsequently, we will discuss the relationship between the prion protein and the cellular response to oxidative stress, attempting ultimately to link PrP function and neurodegeneration in these disorders.

Introduction

Transmissible spongiform encephalopathies (TSEs) form a group of fatal neurodegenerative disorders represented principally by Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler syndrome (GSS), and fatal familial insomnia in humans (FFI), and by scrapie and bovine spongiform encephalopathy in animals [76]. Also called prion diseases, TSEs have the unique property of being infectious, sporadic or genetic in origin [86]. Brain extracts from patients affected by any of these three forms are infectious when inoculated into rodents. The agent responsible for transmission of the disease is thought to be a protein called PrPSc (which stands for the scrapie isoform of the prion protein). PrPSc represents a conformational variant of a normal protein of the host: the cellular isoform of the prion protein, or PrPC. Even though there is not yet a definitive demonstration that PrPSc constitutes, by itself, the agent of TSEs, there is no doubt that transition from PrPC to PrPSc is a crucial pathogenic event. The central role of PrP in TSEs is exemplified by the fact that PrP-null mice are resistant to the disease [18]. Strong genetic linkages between mutations in the PrP gene and genetic forms of TSEs have also been established [76], [82]; moreover, the efficiency of experimental transmission of the disease from one species to another is dependent on the similarity of the PrP sequences between species [105].

In TSEs, neurodegeneration has not always been associated with the presence of PrPSc [17], [59], and a transmembrane form of PrP, called Ctm-PrP [43], as well as a PrP related molecule, Doppel [68], have also been implicated. In any case, it appears that oxidative stress events are involved in TSE pathogenesis leading to the hypothesis that TSEs belong, together with other degenerative disorders, to oxidative stress related diseases (for review see Ref. [97]).

In the present review, we will not discuss the etiologic hypothesis of TSEs, nor detail the data related to the generation of PrPSc. Instead, after giving an overview of prion diseases, we will review the direct and indirect results supporting the involvement of oxidative stress in TSEs. We will then discuss the role of PrP in the cellular defense against this stress, which is particularly relevant considering that conversion into PrPSc could alter this role.

Section snippets

The prion hypothesis

One of the first approaches used in TSEs research was the experimental transmission of the disease to rodents using infected animal brains. Infectivity in these extracts appeared to be highly resistant to treatment altering nucleic acids (formaldehyde, DNAse, RNAse, UV, heat) [46]. In 1982, Prusiner et al. purified these extracts leading to infectious fractions containing mostly proteins. The idea that the agent could be a protein was then put forward and the infectious fractions were called

Oxidative stress susceptibility and activities of anti-oxidant enzymes

The first line of evidence supporting a connection between PrP and oxidative stress arose from studies showing alterations in the cellular response to stress in correlation with PrP expression (Fig. 2) and conversion (Fig. 3).

Since the first cell culture models of infectious TSEs were unstable and complex to use, the toxicity of a peptide corresponding to amino acids 106 to 126 of PrP (PrP106–126) was used by different groups in order to mimic the neurotoxicity of PrPSc [28]. Using this model,

Relationship between apoptosis, PrP and oxidative stress in TSEs

Forloni et al. first reported the presence of apoptotic events in TSEs while exposing rat neuronal primary cultures to PrP106–126 [35]. Later, evidence of apoptosis was demonstrated in vivo in the brain of scrapie-infected sheep [32], in mice and hamster infected with various prion strains [37], [47], [62], [111] and more notably in extracts of brain from patients affected by the disease [30], [39]. In addition, Schatzl et al. reported the detection of apoptotic events in infected mouse

PrP, signaling pathways and oxidative stress

Considering the cell biology of PrPC, the putative role of this protein and its pathogenic isoform on oxidative stress-related mechanisms in TSEs, it is now judicious to review the data concerning the involvement of PrP in signal transduction.

Conclusion

One of the key issues regarding the results presented here is the specificity of the observed signs of oxidative stress in TSEs. Indeed, it is possible to imagine that oxidative stress is a non-specific response of neurons to many kinds of insults, and is only indirectly related to PrP function. This seems unlikely as lack of PrP in several models is clearly linked to alteration of anti-oxidant enzyme functions and increased sensitivity to oxidative stress. As it is still possible that PrPSc

Acknowledgements

We thank Drs. Lisa Héron-Milhavet and Ward Pedersen for the critical reading of the manuscript.

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    Present address: National Institute on Aging, National Institute of Health, Laboratory of Neuroscience, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.

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