Theoretical Analysis of the Implication of PrP in Neuronal Death during Transmissible Subacute Spongiform Encephalopathies: Hypothesis of a PrP Oligomeric Channel (original) (raw)
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2012
P rion diseases comprise a group of rapidly progressive and invariably fatal neurodegenerative disorders for which there are no effective treatments. While conversion of the cellular prion protein (PrP C ) to a β-sheet rich isoform (PrP Sc ) is known to be a critical event in propagation of infectious prions, the identity of the neurotoxic form of PrP and its mechanism of action remain unclear. Insights into this mechanism have been provided by studying PrP molecules harboring deletions and point mutations in the conserved central region, encompassing residues 105-125. When expressed in transgenic mice, PrP deleted for these residues (Δ105-125) causes a spontaneous neurodegenerative illness that is reversed by co-expression of wild-type PrP. In cultured cells, Δ105-125 PrP confers hypersensitivity to certain cationic antibiotics and induces spontaneous ion channel activity that can be recorded by electrophysiological techniques. We have utilized these drughypersensitization and current-inducing activities to identify which PrP domains and subcellular locations are required for toxicity. We present an ion channel model for the toxicity of Δ105-125 PrP and related mutants and speculate how a similar mechanism could mediate PrP Scassociated toxicity. Therapeutic regimens designed to inhibit prion-induced toxicity, as well as formation of PrP Sc , may prove to be the most clinically beneficial.
AJP: Cell Physiology, 2003
A major prion protein (PrP) mutant that forms amyloid fibrils in the diseased brain of patients with Gerstmann-Sträussler-Scheinker syndrome (GSS) is a fragment of 7 kDa spanning from residues 81-82 to 144-153 of PrP. Analysis of ionic membrane currents, recorded with a libid bilayer technique, revealed that the wild-type fragment PrP(82-146) WT and the partially scrambled PrP(82-146) (127-146) SC are capable of forming heterogenous ion channels that are similar to those channels formed with PrP(106-126). In contrast, PrP(82-146) peptides in which the region from residue 106 to 126 had been scrambled (SC) showed a reduction in interaction with lipid membranes and did not form channels. The PrP(82-146) WT- and PrP(82-146) (127-146) SC-formed cation channels with fast kinetics are Cu2+ sensitive and rifampicin (RIF) insensitive, whereas the time-dependent inactivating channels formed by these same peptides are both Cu2+ and RIF insensitive. The presence of RIF in the solution before t...
2011
Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are fatal neurodegenerative disorders present both in human and animals with different aetiology as they can occur genetically, spontaneously or by infection (Prusiner 1998). TSE are caused by the presence of proteinacious aggregates, called ‘prions’, in brains of afflicted individuals. According to the ‘protein-only’ hypothesis, the central event of prion pathogenesis is the conformational change of the cellular protein, PrPC, into its pathological counterpart, PrPSc in a process in which PrPSc acts as a template (Prusiner 1998). Differently from PrPC, mainly constitutes of α-helices, PrPSc is enriched in β-sheets, aggregation-prone and resistant to treatment with proteinase K. Despite the intense research, many questions in prion biology are still open related to both the physiological functions of PrPC and mechanism of the disease caused by the misfolded form PrPSc. Thus, exploring some of these aspect...
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.
In vivo prion models and the disconnection between transmissibility and neurotoxicity
Ageing research reviews, 2017
The primary causative event in the development of prion diseases is the misfolding of the normal prion protein (PrP(C)) into an ensemble of altered conformers (herein collectively denoted as PrP(Sc)) that accumulate in the brain. Prominent amongst currently unresolved key aspects underpinning prion disease pathogenesis is whether transmission and toxicity are sub-served by different molecular species of PrP(Sc), which may directly impact on the development of effective targeted treatments. The use of murine models of prion disease has been of fundamental importance for probing the relationship between hypothesised "neurotoxic" and "transmissible" PrP(Sc) and the associated kinetic profiles of their production during disease evolution, but unfortunately consensus has not been achieved. Recent in vivo studies have led to formulation of the "two-phase" hypothesis, which postulates that there is first an exponential increase in transmitting PrP(Sc) species ...
Prion protein oligomer and its neurotoxicity
Acta biochimica et biophysica Sinica, 2013
The prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. According to the 'protein only' hypothesis, the key molecular event in the pathogenesis of prion disease is the conformational conversion of the host-derived cellular prion protein (PrP(C)) into a misfolded form (scrapie PrP, PrP(Sc)). Increasing evidence has shown that the most infectious factor is the smaller subfibrillar oligomers formed by prion proteins. Both the prion oligomer and PrP(Sc) are rich in β-sheet structure and resistant to the proteolysis of proteinase K. The prion oligomer is soluble in physiologic environments whereas PrP(Sc) is insoluble. Various prion oligomers are formed in different conditions. Prion oligomers exhibited more neurotoxicity both in vitro and in vivo than the fibrillar forms of PrP(Sc), implying that prion oligomers could be potential drug targets for attacking prion diseases. In this article, we describe recent experimenta...
Physiology of the prion protein
2008
diseases are transmissible spongiform encephalopathies (TSEs), attributed to conformational conversion of the cellular prion protein (PrP C) into an abnormal conformer that accumulates in the brain. Understanding the pathogenesis of TSEs requires the identification of functional properties of PrP C. Here we examine the physiological functions of PrP C at the systemic, cellular, and molecular level. Current data show that both the expression and the engagement of PrP C with a variety of ligands modulate the following: 1) functions of the nervous and immune systems, including memory and inflammatory reactions; 2) cell proliferation, differentiation, and sensitivity to programmed cell death both in the nervous and immune systems, as well as in various cell lines; 3) the activity of numerous signal transduction pathways, including cAMP/protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, as well as soluble non-receptor tyrosine kinases; and 4) trafficking of PrP C both laterally among distinct plasma membrane domains, and along endocytic pathways, on top of continuous, rapid recycling. A unified view of these functional properties indicates that the prion protein is a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences upon both physiology and behavior. I. INTRODUCTION: A BRIEF ACCOUNT OF PRION PATHOLOGY A. The Prion Diseases Prion diseases correspond to anatomo-pathologically defined transmissible spongiform encephalopathies (TSEs) of an infectious, genetic, or sporadic nature and are characterized by neurodegeneration and protein aggregation. These diseases include kuru and Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and bovine spongiform encephalopathy (BSE), also known as "mad cow disease," among others. The diseases can affect subjects at distinct age groups, course with a variety of motor or cognitive symptoms, and although their prevalence is relatively low, TSEs are still incurable and invariably fatal (262). The pathogenesis of prion diseases is attributed to major changes in the metabolism of the cellular prion protein (PrP C). Current understanding of TSEs evolved from the concept of the "prion," that is, a proteinaceous, nucleic acid-free, infectious particle (427). 674 LINDEN ET AL.
Interaction between the cellular prion (PrPC) and the 2P domain K+ channel TREK-1 protein
Biochemical and Biophysical Research Communications, 2006
The cellular prion protein (PrP C ) is a highly conserved protein throughout the evolution of mammals and therefore is thought to play important cellular functions. Despite decades of intensive researches, the physiological function of PrP C remains enigmatic. Differently, in particular pathological contexts, generally referred as transmissible spongiform encephalopathies, a conformational isoform of PrP C , i.e., PrP Sc , is considered the causative agent of these diseases. In this study, we investigated putative PrP C cellular functions through the identification of PrP C protein interactants. Using a bacterial two-hybrid approach, we identified a novel interaction between PrP C and a two-pore potassium channel protein, TREK-1. This interaction was further verified in transfected eukaryotic cells using co-immunoprecipitation and confocal microscopic analysis of the fluorescent transfected proteins. Importantly, in the cerebellar cortex, the endogenous PrP C and TREK-1 proteins exhibited co-localization signals in correspondence of the Purkinje cells. Furthermore, a deletion mapping study defined the carboxyl-terminal regions of the two proteins as the possible determinants of the PrP C -TREK-1 interaction. Our results indicated a novel PrP C interacting protein and suggested that this complex might be relevant in modulating a variety of electrophysiological-dependent cellular responses.
2011
Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP C , into a β-sheet-rich, aggregated isoform, PrP Sc. We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the β2-α2 loop in the NMR structure at pH 4.5 and 20 °C, caused transmissible de novo prion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well-ordered β2-α2 loop at 20 °C, elicits spontaneous PrP aggregation in vivo. Transgenic mice expressing PrP D167S developed a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the β2-α2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.