Cross-linking cellular prion protein triggers neuronal apoptosis in vivo (original) (raw)
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Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways
PLoS pathogens, 2015
Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfold...
A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death
The American Journal of Pathology, 2010
Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP , suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(⌬CR) mice , which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein.
Molecular Mechanisms of Neurotoxicity of Pathological Prion Protein
Current Molecular Medicine, 2004
Transmissible Spongiform Encephalopathies or prion related disorders are fatal and infectious neurodegenerative diseases characterized by extensive neuronal apoptosis and accumulation of a misfolded form of the cellular prion protein (PrP), denoted PrP Sc . Although the mechanism of neurodegeneration and the involvement of PrP Sc is far from clear, data indicates that neuronal apoptosis might be related to activation of several signaling pathways, including proteasome dysfunction, alterations in prion maturation pathway and endoplasmic reticulum (ER) stress. In this article we describe recent studies investigating the molecular mechanism of PrP Sc neurotoxicity. We propose a model in which the key step in the pathogenesis of prion disorders, independent on their etiology, is the alteration of ER-homeostasis due to drastic modifications of the physicochemical properties of PrP, leading to the activation of ER-dependent signaling pathways that controls cellular survival.
Prion Proteins and Neuronal Death in the Cerebellum
Prions - Some Physiological and Pathophysiological Aspects
The cellular prion protein, a major player in the neuropathology of prion diseases, is believed to control both death and survival pathways in central neurons. However, the cellular and molecular mechanisms underlying these functions remain to be deciphered. This chapter presents cytopathological studies of the neurotoxic effects of infectious prions and cellular prion protein-deficiency on cerebellar neurons in wild-type and transgenic mice. The immunochemical and electron microscopy data collected in situ and ex vivo in cultured organotypic cerebellar slices indicate that an interplay between apoptotic and autophagic pathways is involved in neuronal death induced either by the infectious prions or by prion protein-deficiency.
Virus research, 2014
The cellular prion protein (PrP(C)), a cell surface glycoprotein involved in prion disorders, has been shown to mediate the toxicity of several pathological aggregates, including its own misfolded state and some oligomeric assemblies of the amyloid β peptide, which are thought to be primarily responsible for the synaptic dysfunction characterizing Alzheimer's disease. Thus, elucidating the physiological function of PrP(C), and how it could be corrupted by the interaction with misfolded proteins, may provide important insights to understand the pathological processes of prion and Alzheimer's diseases, and possibly other neurodegenerative disorders. In this manuscript, we review the data supporting a role for PrP(C) at the intersection of different neurodegenerative diseases, discuss potential mechanisms by which this protein could mediate neurotoxic signals, and examine therapeutic approaches that may arise from the identification of PrP(C)-directed compounds.
Cellular prion protein is essential for oligomeric amyloid- -induced neuronal cell death
Human Molecular Genetics, 2012
In Alzheimer disease (AD), amyloid-b (Ab) oligomer is suggested to play a critical role in imitating neurodegeneration, although its pathogenic mechanism remains to be determined. Recently, the cellular prion protein (PrP C ) has been reported to be an essential co-factor in mediating the neurotoxic effect of Ab oligomer. However, these previous studies focused on the synaptic plasticity in either the presence or the absence of PrP C and no study to date has reported whether PrP C is required for the neuronal cell death, the most critical element of neurodegeneration in AD. Here, we show that Prnp 2/ 2 mice are resistant to the neurotoxic effect of Ab oligomer in vivo and in vitro. Furthermore, application of an anti-PrP C antibody or PrP C peptide prevents Ab oligomer-induced neurotoxicity. These findings are the first to demonstrate that PrP C is required for Ab oligomer-induced neuronal cell death, the pathology essential to cognitive loss.