ReviewOxidative stress and the prion protein in transmissible spongiform encephalopathies
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.
References (111)
- et al.
Inactivation of glutathione peroxidase by nitric oxide. Implication for cytotoxicity
J. Biol. Chem.
(1995) - et al.
Effects of oxidative stress on prion protein expression in PC12 cells
Int. J. Dev. Neurosci.
(1997) - et al.
Prion protein-deficient cells show altered response to oxidative stress due to decreased SOD-1 activity
Exp. Neurol.
(1997) - et al.
Mice devoid of PrP are resistant to scrapie
Cell
(1993) Metals and neuroscience
Curr. Opin. Chem. Biol.
(2000)- et al.
Neurological illness in transgenic mice expressing a prion protein with an insertional mutation
Neuron
(1998) - et al.
Induction of heme oxygenase-1 in the brains of scrapie-infected mice
Neurosci. Lett.
(2000) - et al.
Hippocampal slices from prion protein null mice: disrupted Ca(2+)-activated K+ currents
Neurosci. Lett.
(1996) - et al.
Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106–126 of the prion protein
J. Biol. Chem.
(1994) - et al.
Detection of apoptosis-induced DNA cleavage in scrapie-infected sheep brain
FEMS Microbiol. Lett.
(1994)
Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice
Neuron
Intracellular calcium rise through L-type calcium channels, as molecular mechanism for prion protein fragment 106–126-induced astroglial proliferation
Biochem. Biophys. Res. Commun.
Evidence for oxidative stress in experimental prion disease
Neurobiol. Dis.
Copper binding to the N-terminal tandem repeat regions of mammalian and avian prion protein
Biochem. Biophys. Res. Commun.
Deadly conformations — protein misfolding in prion disease
Cell
Alterations in potassium currents may trigger neurodegeneration in murine scrapie
Exp. Neurol.
Alzheimer’s beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line
J. Biol. Chem.
Expression of cytokine genes and increased nuclear factor-kappa B activity in the brains of scrapie-infected mice
Brain Res. Mol. Brain Res.
Increased ferric iron content and iron-induced oxidative stress in the brains of scrapie-infected mice
Brain Res.
The cellular prion protein (PrP) selectively binds to Bcl-2 in the yeast two-hybrid system
Brain Res. Mol. Brain Res.
Analysis of interaction sites in homo- and heteromeric complexes containing Bcl-2 family members and the cellular prion protein
Brain Res. Mol. Brain Res.
Mutant and infectious prion proteins display common biochemical properties in cultured cells
J. Biol. Chem.
Detection of apoptosis in murine scrapie
Neurosci. Lett.
Cleavage of the amino-terminus of the prion protein by reactive oxygen species
J. Biol. Chem.
A monomer–dimer equilibrium of a cellular prion protein (PrP-C) not observed with recombinant PrP
J. Biol. Chem.
Metal-dependent alpha-helix formation promoted by the glycine-rich octapeptide region of prion protein
FEBS Lett.
Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel
J. Mol. Biol.
A cellular gene encodes scrapie PrP 27–30 protein
Cell
Site-specific and random fragmentation of Cu,Zn-superoxide dismutase by glycation reaction. Implication of reactive oxygen species
J. Biol. Chem.
Effect of scrapie infection on the activity of neuronal nitric-oxide synthase in brain and neuroblastoma cells
J. Biol. Chem.
Insertion in prion protein gene in familial Creutzfeldt–Jakob disease
Lancet
Copper stimulates endocytosis of the prion protein
J. Biol. Chem.
Effect of flupirtine on Bcl-2 and glutathione level in neuronal cells treated in vitro with the prion protein fragment (PrP106–126)
Exp. Neurol.
Prion protein biology
Cell
Ecosystems supporting clusters of sporadic TSEs demonstrate excesses of the radical-generating divalent cation manganese and deficiencies of antioxidant co factors Cu, Se, Fe, Zn. Does a foreign cation substitution at prion protein’s Cu domain initiate TSE?
Med. Hypotheses
Copper(II)-induced conformational changes and protease resistance in recombinant and cellular PrP. Effect of protein age and deamidation
J. Biol. Chem.
Copper converts the cellular prion protein into a protease resistant species that is distinct from the scrapie isoform
J. Biol. Chem.
Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein
J. Biol. Chem.
Gene expression profile in prion protein-deficient fibroblasts in culture
Am. J. Pathol.
Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions
Cell
A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells
J. Biol. Chem.
Scrapie prion protein contains a phosphatidylinositol glycolipid
Cell
Imbalance of antioxidant defense in mice lacking cellular prion protein
Free Rad. Biol. Med.
Identification of a protein that purifies with the scrapie prion
Science
Release of the cellular prion protein from cultured cells after loss of its glycoinositol phospholipid anchor
Glycobiology
Prion protein abrogates Bax-mediated cell death in human primary neuron cultures
Normal host prion protein necessary for scrapie-induced neurotoxicity
Nature
PrPSc-like prion protein peptide inhibits the function of cellular prion protein
Biochem. J.
Prion protein expression and superoxide dismutase activity
Biochem. J.
Antioxidant activity related to copper binding of native prion protein
J. Neurochem.
Cited by (0)
- 1
Present address: National Institute on Aging, National Institute of Health, Laboratory of Neuroscience, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.