[Frontiers in Bioscience 16, 169-186, January 1, 2011]
Understanding the neurospecificity of Prion protein signaling
Benoit Schneider1, Mathea Pietri1, Elodie Pradines1, Damien Loubet1, jean-Marie. Launay2, Odile Kellermann1, Sophie Mouillet-Richard1
1
TABLE OF CONTENTS
1. ABSTRACT
The cellular prion protein PrPC is the normal counterpart of the scrapie prion protein PrPSc, the main component of the infectious agent of transmissible spongiform encephalopathies (TSEs). It is a ubiquitous cell-surface glycoprotein, abundantly expressed in neurons, which constitute the targets of TSE pathogenesis. The presence of PrPC at the surface of neurons is an absolute requirement for the development of prion diseases and corruption of PrPC function(s) within an infectious context emerges as a proximal cause for PrPSc-induced neurodegeneration. Experimental evidence gained over the past decade indicates that PrPC has the capacity to mobilize promiscuous signal transduction cascades that, notably, contribute to cell homeostasis. Beyond ubiquitous effectors, much data converge onto a neurospecificity of PrPC signaling, which may be the clue to neuronal cell demise in prion disorders. In this article, we highlight the requirement of PrPC for TSEs-associated neurodegeneration and review the current knowledge of PrPC-dependent signal transduction in neuronal cells and its implications for PrPSc-mediated neurotoxicity
2. INTRODUCTION
The cellular prion protein PrPC is membrane-anchored protein, whose pathogenic variant, termed PrPSc for scrapie isoform of the prion protein, is the main component of the transmissible agent of spongiform encephalopathies (TSEs). These fatal neurodegenerative disorders include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI) in humans, as well as scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle (reviewed in (1)).
While present in all cell types, PrPC is most abundantly expressed in neurons (2). It is located at the outer leaflet of the plasma membrane, to which it is attached by a glycosylphosphatidylinositol (GPI) moiety. PrPC is subject to heterogeneous glycosylation on two Asn residues and may also undergo proteolytic cleavage. Both types of post-translational modifications yield a variety of isoforms whose distribution may differ according to the cell type, brain region or subcellular compartment considered (3-5). While knock-out studies were much expected to shed light on PrPC function, mice devoid of PrPC turned out to be viable and did not manifest any major abnormality (6). At closer examination, PrPC-deficient mice exhibit increased susceptibility to various types of cerebral insults, including ischemia (7, 8) and seizures (9), and were recently shown to suffer from demyelinating disease (10).
In recent years, much effort has been devoted to unravel the physiological function of PrPC at a cellular level (reviewed in (2)). A converging view is that PrPC may exert diverse roles according to the cellular context and its local environment, notably in relation with its interaction with binding partners. Besides, much evidence now supports the notion that the recruitment of PrPC within multimolecular complexes is associated with cell signaling events, some of which are restricted to neurons (2, 11). Here, we highlight the requirement of PrPC for TSEs-associated neurodegeneration and review the current knowledge of PrPC-dependent signal transduction in neuronal cells and its implications for PrPSc-mediated neurotoxicity.
3. PrPC requirement for PrPSc-associated neurotoxicity
Despite prion replication in many organs and tissues, TSE-induced pathology is restricted to the central nervous system, with widespread neuronal loss, spongiosis, gliosis, and accumulation of PrPSc. It is now quite well established that the autocatalytic conversion of PrPC into PrPSc lies at the root of prion diseases. The central role played by PrPC in the development of prion diseases was first illustrated by the observation that disruption of the PrP gene (Prnp) in mice confers resistance to prion disease and to the propagation of infectious prions (12). Conversely, PrP-overexpressing (tga20) mice exhibit reduced incubation periods as compared to wild-type mice (13). Neurograft experiments carried out on PrP0/0 mice using tga20 mice as brain tissue donors allowed to clearly demonstrate that the presence of endogenous PrPC is mandatory for PrPSc to induce pathological alterations (14). Mallucci et al. further showed that switching off PrPC neuronal expression in infected mice, just prior to the clinical phase, blocks TSE pathogenesis, although abundant prion replication still occurs in glial cells (15). These experiments outline that prions require neuronal PrPC to exert their toxicity. This notion was reasserted and refined in a study based on transgenic mice expressing a GPI anchor-less PrPC (DGPI-PrP) (16). Indeed, DGPI-PrP infected mice were found to efficiently replicate scrapie and accumulate high levels of PrPSc in their brains without any sign of clinical illness. As a whole, these data argue for a primary role of neuronal, GPI-anchored PrPC in prion neuropathogenesis.
How may corruption of GPI-anchored PrPC-associated function(s) in neurons, as a result of the conversion of PrPC into PrPSc, account for prion-associated toxicity? An ongoing debate in the TSE field is whether PrPSc triggers a loss of PrPC physiological function (loss-of-function hypothesis) or promotes a gain of toxic activity (gain-of-function hypothesis), or both (17). This obviously calls for a better understanding of the function held by PrPC in a neuronal context.
4. On the roads to signaling function : PrPC ligands, copper binding, knock-out and crosslinking
4.1. Insight from PrPC partners
That PrPC may act as a receptor or a coreceptor was initially suspected from its location at the cell surface and its orientation towards the extracellular space (18). However, experiments aiming at identifying a soluble ligand of this protein did not succeed. Analyses of the PrPC fold obtained by RMN also failed to reveal any significant structural relationship with well-known receptors, thus hindering the identification of specific ligands for PrPC that would be able to stimulate the protein and recruit signaling effectors. To overcome this limitation, several methodologies and strategies were designed to probe for PrPC partners (reviewed in (2)), including the yeast two-hybrid system (19, 20), chemical cross-linking (21, 22), co-purification with recombinant PrP (23), co-immunoprecipitation (24-26), complementary hydropathy (27), and, more recently, global approaches (28-31).
Among the diverse array of PrPC partners identified thus far, only a few interactions have been shown to bear functional relevance (Table 1). A first class of ligands are involved in ECM adhesion, neuritic extension and maintenance. Among these is the ECM protein laminin (23), a major constituent of the neuronal basal lamina. The PrPC-laminin interaction was shown to sustain neurite outgrowth (32), and at functional level, to promote memory consolidation through PKA and ERK-dependent pathways (33). Of note, we recently introduced the tissue-non specific alkaline phosphatase (TNAP) as a novel protagonist in the PrPC-laminin interplay (26). TNAP specifically interacts with PrPC in the rafts of differentiated bioaminergic neuronal cells. By controlling the phosphorylation state of laminin, TNAP impacts on its ability to interact with PrPC (26) and to support neurite maintenance (our unpublished observations). An additional potential player in the PrPC-laminin complex is the transmembrane protein -dystroglycan depicted both as a PrPC (25) and laminin (34) partner, which joins the extracellular matrix to the cell cytoskeleton. A less well-studied PrPC interaction is that to vitronectin, also involved in axonal growth (35). Finally, the association of PrPC with NCAM in hippocampal neurons promotes the recruitment of both proteins to rafts and Fyn-dependent neurite outgrowth (36).
Other interactors may contribute to endocytosis of PrPC, and that of its pathogenic isoform. A salient example is the laminin receptor (LR) and its precursor (LRP) (19, 37). The pathophysiological implications of the LRP/LR interaction with PrPC have been reviewed elsewhere (38). Two other potently important players in PrPC endocytosis are the transmembrane protein LRP1 (39-41) and the GPI-anchored heparan sulfate proteoglycan glypican 1 (42, 43). How these proteins may contribute to the induction and/or desensitization of PrPC-dependent signal clearly deserves further investigation.
It is also of note that PrPC may interact with itself (44), supporting the possible occurrence of cis or trans interactions, or the binding of soluble PrP to cell-attached counterparts. Soluble PrPC may alternatively serve as a ligand for (a) yet-to-be-identified receptor(s). This hypothesis is notably supported by the work of Chen et al (45) showing that recombinant dimeric PrPC (PrP-Fc) activates signal transduction pathways sustaining neuroprotection and neurite outgrowth in primary cerebellar neurons. While Kanaani and coworkers confirmed the induction of neuronal polarity and synapse formation following exposure of primary hippocampal neurons to recombinant PrPC (46), the nature of the cell surface receptors relaying this effect still is elusive.
One candidate is the stress-inducible 1 (STI-1) protein. Following its identification as a putative PrPC receptor (27), this protein has been further characterized as a soluble trophic factor released from astrocytes (47), whose interaction with PrPC promotes neuronal survival and neuritogenesis through PKA and ERK-dependent pathways (reviewed in (48)).
The growing list of PrPC interactors now includes the Alzheimer's disease associated peptide A-beta (31). While debated (49), the notion that PrPC may serve as a cell-surface receptor for A-beta clearly raises new prospects as to prion and A-beta-mediated signaling and toxicity.
Finally, global approaches have recently allowed to grasp the prion protein interactome in in vitro and in vivo conditions, to define PrPC as a component of multiprotein complexes and to enlarge the PrPC signalosome (28-30, 50). In line with a role for PrPC in the maintenance of myelin integrity (10), novel PrPC interactors include families of neuronal glycoproteins and myelin-associated proteins (29). Two metal ion transporters of the ZIP family have also been identified as PrPC partners (50). ZIP6 and ZIP10 display a PrP-like amino acid sequence within their N-terminal extracellular domain, thus supporting the view of an involvement of PrPC in the transmembrane transport of divalent cations. Of note, bioinformatics tools reveal that the complex molecular network of PrPC and interactors has connections with AKT, JNK and MAPK signaling pathways that are essential for cell survival, differentiation, proliferation or apoptosis (28).
4.2. Copper binding and cleavage
Beyond its interaction with diverse partners, several lines of evidence suggest that the PrPC-dependent recruitment of cell signaling cascades may be promoted by its binding to copper ions and subsequent cleavage. The interplay between PrPC copper binding, cleavage and signaling has been extensively reviewed in Haigh et al (51) and will not be discussed further here. Of note, these aspects of PrPC signaling may be connected with its interaction with various partners, as notably suggested from its association with the cell surface metalloprotease ADAM 23 (52) and discussed by (51).
4.3. The knock-out approach
While the knock-out of PrP in mice did not yield any significant contribution to the elucidation of prion-associated signaling, it has nevertheless led to the isolation of neuronal cell lines devoid of PrPC, which have allowed to shed some light on PrPC-associated signal transduction (reviewed in (53)). A PrP-null hippocampal cell line was notably exploited to establish a correlation between the expression level of PrPC and PI3 kinase activity (54). The lack of PrPC expression appears to be also associated with increased sphingomyelinase activity (55).
In contrast to the mouse model, a clear-cut loss-of-function phenotype was documented in the zebrafish (56). Unlike mammals, the zebrafish possesses two prion protein homologues. Knock-down of PrP-1 causes developmental arrest at the gastrulation stage, with defects in src kinase-dependent calcium signaling and cell adhesion. Besides, an involvement in neuronal development is specifically described for PrP-2. The signaling cascades sustaining the neurogenic role of PrP-2 remain to be elucidated (57).
4.4. The crosslinking paradigm
To bypass the multiplicity of PrPC partners and assess intracellular signaling events associated to this protein, we designed an antibody-based strategy (Figure 1) to promote the clustering of PrPC and thereby trigger an input signal (24). It is now quite well established that PrPC crosslinking at the surface of neuronal or non neuronal cells (11, 58) promotes the recruitment of signaling cascades. Whether antibody-mediated ligation mimics the interaction with a partner (see above) or PrPC dimerization (59), it allows to transiently freeze a PrPC-containing signaling platform able to activate sub-membrane effectors. Of note, this property is intimately connected with the location of PrPC within rafts, as further discussed in Chapter 6 and reviewed in (60).
5. PrPC signaling in neurons : a combination of ubiquitous and neurospecific effectors and pathways
Understanding the neurospecificity of prion protein signaling is experimentally challenging since it necessitates the availability of appropriate in vitro models. Our own strategy has been to exploit an inducible neuroectodermal cell line (1C11), able to convert into fully functional serotonergic (1C115-HT) or noradrenergic (1C11NE) neuronal cells upon induction, in a homogenous and synchronous manner (61). 1C11 cells endogenously express PrPC at comparable levels whatever their differentiation state (62), and thus represent a valuable tool to analyze PrPC function in relation with the onset, maintenance and homeostasis of a neuronal phenotype. Based on our overall findings obtained with the 1C11 cell line and those from the literature, our current view is that PrPC signaling within a neuronal context shares commonalities with that in other cell types. It also bears neuronal specificity, that may depend on isoforms, partners, cell compartmentation, neuronal polarity (see Chapter 6) and may account for the neurotoxicity of pathogenic prions.
5.1. NADPH oxidase activation, Reactive Oxygen Species production and redox equilibrium
NADPH oxidase was identified as an intracellular effector recruited upon antibody-mediated PrPC ligation in 1C11 precursor cells and their neuronal progenies but also in GT1-7 neuroendocrine cells and BW5147 T lymphocytes (63). NADPH oxidase is an oligomeric enzyme composed of a catalytic core (NOX) and adapter subunits (p47PHOX, p67PHOX, p22PHOX, rac) that assemble at the plasma membrane or at the surface of endosomes and catalyzes the conversion of O2 into superoxide anion O2.- (64). Both p47PHOX and p67PHOX subunits are phosphorylated following PrPC ligation (63). Although the detailed mechanisms through which PrPC activates NADPH oxidase remain unclear, we depicted an involvement of PI3 kinase (PI3K) and Protein kinase C delta (PKC delta) (11) in the PrPC-dependent control of NADPH oxidase (Figure 2).
In contrast to oxidative stress conditions where Reactive Oxygen Species (ROS) saturate antioxidant defenses, the PrPC-induced production of ROS by NADPH oxidase is transient and devoid of toxicity. The ubiquitous PrPC-NADPH oxidase-ROS cascade thus introduces PrPC as an important regulator of cellular redox equilibrium.
The free radical properties of the superoxide anion O2.- and other ROS derived from O2.- allow ROS to covalently modify macromolecular molecules, like proteins, lipids and nucleic acids (65). As second message signals, ROS have emerged as regulators of many redox-sensitive protein activities. Accordingly, our search for downstream targets of the PrPC-ROS coupling has lead to the identification of the MAP kinases ERK1/2 (63) and the metalloprotease TACE (66) as effectors of PrPC signaling.
5.2. ERK1/2 MAP Kinases, cell survival and homeostasis
The ERK1/2 MAP kinases have been documented as targets of PrPC signaling in many different cell lines and experimental paradigms. A PrPC-ERK1/2 coupling was notably evidenced in the 1C11 neuronal cell line (63), primary neurons (45, 67), neuroendocrine cells (63, 68) and various types of immune cells (58, 63). Diverse strategies have converged onto a biochemical link between PrPC and ERK1/2 activation, including antibody-mediated ligation of PrPC (63, 68), cell exposure to recombinant PrP-Fc (45), soluble STI-1 (69) or blockade of the PrPC-laminin interaction in vivo (33). It is of note that, in physiological settings, PrPC does not couple to JNK and p38, two stress-associated protein kinases that appear to contribute to the neurotoxicity of pathogenic prions or their PrP106-126 peptide mimetics (63, 70, 71).
At a mechanistic level, relatively few studies have addressed the issue of the molecular cascades relaying the PrPC-dependent activation of ERK1/2. We were able to show an involvement of ROS, downstream from NADPH oxidase, in the control of ERK1/2 phosphorylation. This fits in with the notion that ROS, as signaling transducers, promote kinase activation and trigger phosphatase inhibition (72, 73). While ROS thoroughly control ERK1/2 activation in non-neuronal cells, they only partly contribute to the phosphorylation of these MAP kinases in a neuronal context (63). This prompted us to postulate the recruitment of a neuronal-specific cascade downstream from PrPC that would additionally converge onto ERK1/2 (Figure 2). This second cascade may involve the Shc-Grb2/Sos-Ras-Raf pathway, whose role in ERK1/2 activation has been largely documented (74, 75). In this respect, it is of note that PrPC binds Grb2 in neuronal cells (20).
The functional link between PrPC and the pleiotropic ERK1/2 MAP Kinases (76) strengthens the view that PrPC participates to cell survival and homeostasis and that this pathway may account in part for the ubiquitous protective role exerted by PrPC against diverse insults (77).
5.3. The CREB Transcription factor
The contribution of ERK1/2 to cell homeostasis is assumed to be relayed by transcription factors including AP1, Elk-1, NF-kB or CREB. CREB, for cAMP-responsive element binding protein, is activated in response to several stimuli, including growth factors, hormones, inflammatory cytokines or neurotransmitters and triggers the transcription of genes involved in cell survival, differentiation, proliferation or neuronal plasticity (78, 79). With the 1C11 cell line, we identified CREB as a downstream effector of the PrPC-ERK pathway, in both undifferentiated and neuronal cells (80).
The PrPC-dependent activation of CREB results in the transcription of two immediate early genes (IEG) : egr-1 and c-fos (80) (Figure 2). Egr-1 and c-fos are transcription factors that relay the action of CREB in cell survival and proliferation (81). The identification of a functional link between PrPC-CREB-Egr-1/c-fos in 1C11 precursor cells as well as in 1C11 neuronal derivatives indicates that PrPC may exert a ubiquitous role in the control of cell homeostasis. CREB inhibition or c-fos deletion in mice alter nerve excitability and trigger neurodegeneration in stress conditions (82, 83). Besides, the signaling pathway CREB-Egr-1/c-fos is indeed involved in long-term potentiation and memory consolidation (84). Within a neuronal context, the coupling of PrPC to CREB and PrPC-induced egr-1/c-fos transcription may thus reflect some contribution of PrPC to synaptic plasticity.
6. Neuronal specificity of PrPC signaling
6.1. Neuronal specificity of PrPC signaling : a matter of isoforms ?
Despite the identification of PrPC-controlled signaling effectors (PI3 kinase, NADPH oxidase, ERK1/2, CREB) shared by neuronal and non-neuronal cells, much evidence points to a neurospecific action of PrPC, which may be the clue to PrPSc-mediated neurotoxicity.
The neuronal signature of PrPC signaling may be accounted for by the selective expression of some prion protein isoforms in particular neuronal compartments (85). In agreement, we observed differences in the set of PrPC glycoforms expressed in the 1C11 neuronal cell line according to the differentiation state (86). However, there is no strategy to specifically monitor the cell signals imparted by a given isoform of PrPC. The use of antibodies targeting various epitopes may help discriminate between some subsets of PrPC (Figure 1). The comparable NADPH oxidase-dependent ROS production or ERK1/2 activation obtained with antibodies against either the carboxy- or the amino-terminus of PrPC (63) leads us to propose that both truncated and full-length PrPC are competent to transduce protective signals. Notwithstanding, the copper-binding N-terminal region of PrPC may be critical for mobilizing some cell survival signals, as suggested from in vitro (54) and in vivo (87, 88) observations. The 95-125 central region further deserves special consideration. Indeed, not only does it overlap the cleavage site (Figure 1) but it also encompasses the dimerization domain (59). This may explain the massive apoptosis of hippocampal neurons observed upon in vivo cross-linking of PrPC with antibodies targeting the 95-105 epitope of the protein (89). A critical role imparted by this PrP region may also be inferred from the very severe neurodegenerating phenotype observed in mice with a deletion in the central domain (∆105-125 or ∆94-134) (90, 91).
The notion of neurospecific isoforms cannot be disconnected from that of partners. Indeed, in line with the notion that PrPC may drive the assembly of multicomponent complexes at the cell surface allowing for the instruction of cell signaling events (2), a specificity of PrPC-containing platforms according to the cell type and subcellular microdomain is very likely.
6.2. The PrPC-Caveolin-Fyn signaling platformA salient example of a cell-type specific formation of a PrPC-containing complex is the implementation of a platform associating PrPC, the raft component caveolin and Fyn, a member of the Src tyrosine kinase family, that is restricted to the neuronal progenies of the 1C11 cell line (24). In 1C11 cells, PrPC, caveolin and Fyn are expressed at similar levels whatever the differentiation state, but their functional association is specific to cells that have acquired a complete mature serotonergic or noradrenergic neuronal phenotype. This restriction may in part relate to the onset of neuronal polarity since the coupling of PrPC to Fyn only occurs in neurites of fully differentiated neuronal cells, while PrPC expressed at the surface of the cell body weakly activates Fyn. One explanation for this neuronal and sub-cellular restriction may be the contribution of specific PrPC isoforms or partners to the activation of Fyn. Another possible important parameter is the local membrane composition. The spatial organization of receptors, transporters, scaffold proteins... within microdomains (caveolae, rafts) governs many aspects of signal transduction (92). The specific lipid composition of rafts indeed allows for stable and effective interactions between cell signaling partners. Beyond their importance for prion protein trafficking and conversion into PrPSc, lipid rafts indeed drive PrPC signaling (reviewed in (60)).
A frequently raised issue is how GPI-anchored proteins may transduce intracellular signals. It is now acknowledged that the crosslinking of cell surface proteins by antibodies may induce the clustering of rafts and thereby initiate cell signaling events (60, 93). The raft constituent caveolin may play an important role in these processes (94). Accordingly, although it lacks any extracellular domain, converging evidence defines caveolin as a major relay in the PrPC-dependent activation of Fyn (24, 67). For instance, immunosequestration of caveolin hinders the activation of Fyn in response to PrPC (24). Also supporting the importance of rafts in PrPC signaling is the observation that PrPC recruits NCAM to lipid rafts to trigger Fyn activation and neurite outgrowth (36).
As summarized in Figure 1, the neurospecific PrPC-caveolin-Fyn platform controls the recruitment of downstream ubiquitous effectors : PI3 kinase, NADPH oxidase, ERK1/2 and CREB (11, 63, 80). Fyn therefore appears as a proximal effector of PrPC that orchestrates the repertoire of signaling cascades coupled to PrPC in neurons.
6.3 Linking PrPC signaling to synaptic plasticity : MMP-9 and beta-dystroglycan
A further aspect of PrPC neurospecific action is associated with extracellular matrix remodeling. Recently, we documented a decrease in the level of MMP-9 encoding mRNAs following antibody-mediated ligation of PrPC that is restricted to the neuronal progenies of the 1C11 cell line (80). The downregulation of MMP9 transcripts is accompanied by a raise in the mRNA level of TIMP-1, the main MMP-9 physiological inhibitor. While both events depend on the coupling of PrPC to CREB, the mechanisms through which PrPC interferes with MMP-9 transcription downstream from CREB remain elusive.
There are multiple potential targets of MMP9 in neurons, among which laminin, growth factors (95) and beta-dystroglycan (96). Beta-dystroglycan, is a transmembrane protein that bridges the extracellular matrix to the cell cytoskeleton and whose cleavage triggers a loss of cell adhesion to its substratum (97). Building upon the observation that beta-dystroglycan interacts with PrPC in the brain (25), we established that PrPC signaling protects beta-dystroglycan from cleavage by MMP-9, as a result of inhibition of MMP-9 transcription and reduced MMP-9-associated proteolytic activity (80). This may enhance the interaction between dystroglycan and laminin (34). By down-regulating MMP-9 expression and activity, it is likely that PrPC contributes to the stability of cell/matrix interactions and improves synaptic activity.
Beyond the regulation of beta-dystroglycan cleavage, the PrPC-dependent control on MMP-9/TIMP1 expression may also account for the neuroprotective role exerted by PrPC. In cerebral ischemia, tissue damage is largely associated to an increase in MMP-9 activity (98). The size of infarct of the ischemic brain is reduced in MMP-9-null mice and, conversely, enlarged in PrP knockout mice (8, 99). On another hand, CREB activation, TIMP-1 expression or PrPC overexpression facilitates neuronal recovery (7, 98, 100). The functional link between PrPC, CREB and MMP-9 may thus constitute one of the facets of PrP neuroprotective action.
6.4. PrPC and neuromodulation: TACE-dependent TNF-alpha shedding and bioamine metabolism
Starting from the coupling of PrPC to ROS production, we recently identified the TNF-alpha Converting Enzyme (TACE) metalloprotease as a novel target of PrPC signaling in neuronal cells (66). Indeed, TACE activation notably necessitates oxidoreduction reactions that unmask a catalytic cystein residue (101). TACE primarily catalyzes the cleavage and shedding of membrane-anchored pro-TNF-alpha into soluble TNF-alpha. Accordingly, antibody-mediated PrPC ligation triggers a time-dependent accumulation of TNF-alpha in the surrounding medium of bioaminergic neuronal cells. TNF-alpha is essentially viewed as a proinflammatory cytokine but it may also act as a modulator of neuronal functions (102). It exerts pleiotropic roles through its binding to two distinct receptors : TNFR1, assumed to transduce pro-apoptotic signals, and TNFR2, associated with cell survival (103). The picture may in fact be more complex since TNF-alpha-mediated activation of TNFR1 can mobilize various signaling pathways resulting in either a survival or a death response, according to compartmentalization (104).
In our experimental paradigm, TNF-alpha shed upon PrPC stimulation does not affect cell viability (66). In support of an action as a neuromodulator, we reported that TNF-alpha triggers the degradation of bioamine neurotransmitters in 1C11-derived neuronal cells.
All these cell signaling events are under the control of the PrPC-caveolin-Fyn platform (Figure 2), indicating that TACE activation and TNF-alpha release occurs at the neurites of differentiated cells. The mechanisms by which TNF-alpha stimulates neurotransmitter catabolism remain unknown. Nevertheless, linking PrPC to neurotransmitter metabolism provides additional support for a key role of PrPC in the regulation of neuronal functions and synaptic activity. PrPC-induced degradation of bioamines likely impacts on the content of neurotransmitter at the synapse and therefore modulates synaptic transmission. Increases in bioamine turn-over (i.e. variations in the concentration ratios of serotonin or norepinephrine vs their respective catabolites) in the hippocampus are assumed to be associated with a control of long term memory consolidation (105-107).
Thus, the identification of the PrPC coupling to TACE-mediated TNF-alpha shedding and bioamine degradation defines a molecular basis that may account for the contribution of PrPC to long-term memory consolidation processes (33, 108). Further, in view of the relationship between synaptic plasticity and sleep (109), this cascade may also sustain the involvement of PrPC in sleep regulation that is inferred from observation in PrP-/- mice (6, 109, 110).
6.5. The interaction with TNAP : physiological implications
In an alternative approach to get insight into the function exerted by PrPC in neurons and in relation with its raft location, we sought to identify proteins that would specifically interact with PrPC in rafts of the neuronal progenies of the 1C11 cell line. Raft isolation and co-immunoprecipitation allowed us to establish an interaction of PrPC with the Tissue-Non specific-Alkaline-Phosphatase (TNAP) (26). This phosphatase has recently been recognized as an important enzyme in the central nervous system, which may contribute to neurotransmission (111). TNAP notably emerges as an important player in bioaminergic neurons since it indirectly contributes to the regulation of serotonin and norepinephrine synthesis by regulating the level of pyridoxalphosphate, a cofactor necessary to aromatic acid decarboxylase (AADC) activity (26).
We further assessed the functional outcome of the association of PrPC with TNAP, focusing on the ecto-phosphatase activity of the enzyme. TNAP acts on phospho-laminin and, by maintaining laminin in a non-phosphorylated state, it favors the interaction of this ECM protein with PrPC. In line with the notion that the binding of laminin to PrPC supports neurite outgrowth, our unpublished data indicate that neurite retraction occurs when the PrPC-laminin interaction is destabilized following an inhibition of TNAP activity.
6.6. From effectors to functions : neuroprotection, neurite outgrowth and plasticity, myelin maintenance
The neuroprotective action of PrPC is well-described (2). PrPC upregulation is notably proposed to sustain post-traumatic recovery of the ischemic brain (7, 8). The neuroprotection afforded by PrPC appears to be imparted by its N-terminal region (88, 112), and may involve various effectors including PI3K and Akt (113). An interference with the p53 pathway has also been described (112). A neuroprotective action of PrPC is also triggered in response to its binding to STI-1, (48), or through trans-interactions (45), both via PKA.
As already discussed, the interaction of PrPC with various of its partners including laminin, NCAM, STI-1 and TNAP supports neurite outgrowth and maintenance (see Chapter 4). On another hand, several lines of evidence point to Fyn and the ERK pathway as important mediators relaying the role of PrPC in neuritic elongation (36, 45, 46, 48). The PrPC-induced phosphorylation of stathmin, which inhibits the microtubule destabilizing activity of the latter protein, may also mirror a role for PrPC in the plasticity of the neuronal architecture (68).
Finally, studies in knock-out mice recently uncovered a role for PrPC in the maintenance of myelin in peripheral nerves (10). The molecular pathways sustaining this action remain to be identified. In line with this, PrPC appears to form complexes with myelin-associated proteins (29).
6.7. PrPC and copper
Work over the past fifteen years has unveiled a very complex interplay between copper, PrPC and signaling (reviewed in (51)). Copper may notably influence PrPC expression, cleavage, interaction with partners and, thereby, signaling. In neuronal cells, it has been proposed that PrPC may regulate the concentration of copper at the synapse (114). In addition, PrPC appears to protects neurons against copper toxicity through its capacity to redox cycle divalent copper into monovalent copper ions (reviewed in (51)).
6.8. Calcium homeostasis
A link between PrPC and calcium influxes has been established in various cell types including neurons and lymphocytes (reviewed in (2)). In the zebrafish embryo, the PrP-mediated increase in intracellular calcium is relayed by src kinases and sustains cell adhesion (57). Similarly, the src kinase Fyn controls calcium influxes downstream from PrPC in hippocampal neurons (115). Besides, hippocampal neurons from PrP-/- mice exhibit a reduced calcium influx via L-type voltage-gated calcium channels (VGCCs), as compared to PrP-expressing neurons (116). The involvement of PrPC in calcium homeostasis is again consistent with a role in synaptic transmission and plasticity. At present, the neuronal response to the PrPC-mediated calcium signals is however still unclear. Diverse outcomes may be investigated, including regulation of the activity of calcium sensing proteins, calcium-dependent gene transcription, or functional interaction with other cell signaling pathways (117).
6.9. The GPCR connection
As mentioned, the cellular prion protein concentrates within specialized membrane microdomains (60), where its interaction with caveolin is critical for instructing downstream cell signaling events in neuronal cells (see Chapter 6.2). Rafts also play a major role in neurotransmitter receptor signaling (118). Assuming that PrPC might reside in close proximity to neurotransmitter receptors within lipid rafts, we exploited the 1C11 cell system to probe an impact of antibody-mediated engagement of PrPC on the signaling activity of the serotonergic receptors present at the cell surface of 1C115-HT neuronal cells. These three serotonergic receptors (5-HT1B/D, 5-HT2B and 5-HT2A) are metabotropic receptors coupled to G-proteins (GPCR). Most, but not all, of their effectors are recruited downstream from G-proteins. We observed a neutral effect of PrPC ligation on the couplings of the 5-HT2B receptor subtype to neuronal nitric oxide synthase (nNOS), which is G-protein independent (119), and to NADPH oxidase, whose intermediates are still unclear (66). In contrast, concomitant PrPC ligation and agonist stimulation of each receptor impacts on the G-protein couplings of the receptor (119). The positive or negative action of PrPC depends on the G-protein and the pathway considered. For instance, PrPC ligation downregulates the Gi-mediated function of the 5-HT1B/D receptor. It also impairs the 5-HT2A receptor-dependent phospholipase C (PLC)-inositol trisphosphate (IP3) response, which is relayed by Gq proteins. This inhibitory effect is somewhat reminiscent of the defects in acetylcholine receptors coupling to Gq induced by accumulation of the A-beta amyloid peptide (120). On another hand, PrPC enhances the Gz-dependent coupling of the 5-HT2B receptor to phospholipase A2 (PLA2) (119). By modulating the signaling activity of the three serotonergic receptors, PrPC affects the cross-talks occurring between the receptors. In fine, the function of 5-HT2B receptors is enhanced while that of 5-HT1B/D receptors is blocked. Because 5-HT1B/D receptors act at a presynaptic level to limit neurotransmitter release (121), our hypothesis is that PrPC reinforces neuronal activity.
As observed for its proper neurospecific couplings (see Chapter 6.2), the modulatory effect of PrPC on serotonergic GPCR function is restricted to mature neuronal cells and caveolin-dependent (119). The involvement of caveolin allows to propose some mechanistic explanation for the action of PrPC. Caveolin interacts with diverse protagonists of GPCR signaling, including GPCRs themselves (122), G proteins (123), or GPCR-related kinases (GRK) (124). The spatio-temporal availability of proximal effectors (e.g. G proteins) and other partners of signaling, such as arrestins, GRKs, or regulators of GPCR signaling (RGS) greatly influences the duration and strength of GPCR signaling (125). By mobilizing caveolin, PrPC ligation most likely interferes with the recruitment of such GPCR partners and in fine modulates the intensities and/or dynamics of G protein activation by the agonist-bound serotonergic receptors.
Whether PrPC exerts similar regulatory action on other types of GPCR in different neuronal populations clearly deserves further attention. Notwithstanding, our data obtained in serotonergic neurons fully fit in with in vivo evidence for an involvement of PrPC in the homeostasis of the brain serotonergic system (110).
7. PrPSc neurotoxicity : evidence for a subversion of PrP signaling
7.1. Prion-induced neurotoxicity : a loss of neuroprotective signals ?
Our understanding of the mechanisms underlying PrPSc-induced neurodegeneration still is far from complete. In view of the requirement of PrPC for the neurotoxic action of PrPSc, as summarized in chapter 3, it is now admitted that neuronal demise in TSEs primarily originates from alterations of PrPC function(s). The � loss-of-function hypothesis � posits that PrPSc behaves as a dominant negative and disrupts PrPC signaling. This scheme accommodates well with the increased sensitivity of PrP-depleted neurons to various types of insults, as compared to PrP-expressing counterparts (reviewed in (126)). The loss of PrPC neuroprotective function in an infected context may also be accounted for by the inability of PrPSc to undergo proteolytic cleavage at position 111/112 (127) and thereby to generate the PrP N-terminal fragment endowed with neuroprotective activity (112).
It is generally claimed that the loss-of-function hypothesis cannot fully account for PrPSc-mediated neurodegeneration since PrP knockout mice are viable and do not exhibit any sign of brain neurodegeneration (128). A more severe phenotype of PrP null mice may nonetheless be masked by regulatory mechanisms that compensate PrPC silencing during embryogenesis and development. Irrespective of compensation, using behavioral tests in mice, we observed that some of the deficits progressively induced by prion infection recapitulate phenotypic changes monitored in PrP knock-out animals (110). It is finally noteworthy that the neuroprotective role exerted by PrPC in vivo mostly manifests under stress conditions (6). Whether prion infection increases the vulnerability to brain insults such as ischemia or stroke has not been tested so far.
7.2. Evidence towards the gain of function hypothesis
Comparatively to the loss of function hypothesis, there is much more experimental evidence to support the gain of function model. In this scheme, it is proposed that PrPSc exacerbates PrPC signals to toxic levels (17). Mechanistically, this could arise from an increased stability of PrPSc-containing signaling complexes. This is directly supported by in vivo observations obtained in transgenic mice overexpressing wild type PrPC by 5 to 10-fold (129). In these mice, the aggregation of normal PrPC is associated with synaptic loss and a neurological disease that is not transmissible. Besides, in line with the role of rafts in normal PrPC signaling (see Chapter 6.2 and (60)), drugs that disrupt the integrity of rafts impair the toxicity of prions in neuronal cells (130). It is further proposed that the infection of neurons triggers a durable aggregation of signaling platforms within rafts where PrPC is replaced by its pathogenic isoform (131).
7.2.1. Can the gain-of-function hypothesis be tested in vivo?
The validity of the gain of function hypothesis is difficult to address in vivo, notably because TSEs are chronic disorders with very long latencies. Global analyses indicate that the changes induced by prions in the brain vary according to the stage of disease incubation and to the prion strain (132). In regard to the effectors and pathways of PrPC signaling in neuronal cells (Chapter 6), it is noteworthy that increases in the activation states of Fyn (133) and ERK1/2 (134) in the brains of infected mice have been reported. Finally, the occurrence of oxidative stress in prion diseases is well-established, both in animal models and patients (135-138). The primary origin of uncontrolled ROS production cannot however be traced in vivo. Other pathways (NFkappaB (139), PLD, (140)) are altered in prion infected mice and may provide candidate targets of PrPC normal signaling in neurons.
7.2.2. Lessons from the Prion peptide PrP 106-126
Cellular models offer an alternative approach to overcome the complexity of in vivo studies. In some prototypic assays, the toxicity of PrPSc is mimicked by the PrP106-126 prion peptide. PrP106-126 shares several physicochemical properties with PrPSc, including a beta-rich structure and the capacity to aggregate. Our work with the 1C11 cell line has allowed to shed some light on the detrimental events triggered by PrP106-126 (70). In line with the neurospecificity of PrPC signaling, the toxicity of PrP106-126 to 1C11 cells is restricted to neuronal serotonergic or noradrenergic progenies and is relayed by PrPC and its downstream effectors (70). Notably, PrP106-126 triggers a NADPH oxidase-dependent chronic production of ROS that saturates the cellular antioxidant capacity. These oxidative stress conditions are associated with the prolonged and sustained phosphorylation of ERK1/2, the activation of the stress-activated kinases JNK and p38 and cell apoptosis (70). Similar cascades appear to operate in primary cortical neurons (71) and SH-SY5Y neuroblastoma cells (141, 142).
If PrP106-126 allows to unveil some mechanisms of prion-induced neurotoxicity, it obviously cannot fully mimic PrPSc-induced neurodegeneration. PrP106-106 is neurotoxic but not infectious and the kinetics of cell events induced by the prion peptide are not compatible with the high latency of prion diseases that may range between a few months up to several decades. Rather, the cascades monitored in cells exposed to PrP106-126 may reflect the acute response to pathogenic prions.
7.2.3. The contribution of chronically-infected cells
Despite the availability of diverse cellular models of prion infection (143), there is still little information on the cellular and molecular impact of pathogenic prions on neuronal physiology. In GT1-7 neuroendocrine cells, infection is associated with reduced viability (144) and increased susceptibility to oxidative stress (145). Primary cerebellar granule neurons infected by several prion strains also exhibit increased rates of apoptosis (146). The ability of neurospheres to propagate prions (147-149) may offer a promising tool to assess prion-induced cellular dysfunctions. The 1C11 neuronal cell line also can replicate several prion strains (150). In these cells, endogenous PrPC expression is sufficient to sustain chronic infection. PrPSc accumulation does not induce any major phenotypic change in 1C11 undifferentiated cells. Prion-infected 1C11 cells retain the ability to engage into serotonergic or noradrenergic differentiation programs. However, we monitored specific alterations of the overall neurotransmitter-associated functions in the bioaminergic neuronal progenies of 1C11 infected cells. The decreases in neurotransmitter synthesis, storage and transport and the increases in neurotransmitter catabolism are reminiscent of the serotonergic dysfunctions reported in TSE-affected animals or patients (110, 151). Of note, we detected the production of oxidized derivatives of either serotonin or catecholamines that are classified as neurotoxins and alter neuronal function (150). The formation of serotonin and catecholamine oxidation products clearly mirrors elevated levels of ROS in prion-infected neuronal cells. We favor the view that the enhanced ROS level originates from a deviation of the PrPC coupling to the ROS-generating enzyme NADPH oxidase (Figure 3) (63).
A subversion of the signaling pathways downstream from the PrPC-caveolin-Fyn complex on neuronal processes would be in line with the neuritic transport of PrPSc in infected cells (152). It could also account for the occurrence of synaptic dysfunction and dendritic atrophy prior to neurodegeneration in TSEs (153).
8. CONCLUSIONS AND FUTURE DIRECTIONS
Considerable advance has been made over the past years on the relationship between the toxicity of PrPSc and the normal function of its cellular counterpart PrPC in neurons. The binary model according to which PrPSc may promote either a loss or a gain of PrPC function is clearly oversimplistic. Indeed, it does not take into account the multiplicity of PrPC isoforms, which may not all be equivalent substrates for conversion into PrPSc. The relative contribution of a given isoform to the overall signaling events associated to PrPC is another important parameter, which is very difficult to challenge experimentally. Adding to this complexity is the notion that the subset of PrPC species eligible for PrPSc formation varies according to the prion strain. Finally, in view of the diversity of PrPC partners, it is likely that the conversion into PrPSc exerts promiscuous impact on the PrPC interactome. For all these reasons, a combination of loss and gain of PrPC activity upon prion infection appears more realistic. The outcome of PrPSc accumulation on PrPC function may not only depend on the isoform, signaling complex, effectors and cell type considered. It may also evolve in time and space, as notably suggested by longitudinal studies in infected animals at a global scale.
Despite the progress achieved, there are still many questions to be answered. What is the significance of the plethora of PrPC isoforms? Why can PrPSc be found in normal brain without any sign of pathology (153)? How can we reconcile the critical role of the caveolin-Fyn platform in PrPC signaling and the normal transmission of TSEs to mice deficient for caveolin or Fyn (154)?
As highlighted in this review, the continuous synergy of multidisciplinary in vivo and in vitro approaches will be mandatory for deciphering the complexity of the mechanisms sustaining prion-induced neurodegeneration. The reciprocal and evolving dialogue between infected neurons and the surrounding glia cells is an important issue to address. Another challenge is to diagnose some of the prion-induced brain dysfunctions at a stage when therapy can be effective.
This quest in fact extends beyond the TSE field. Intricate networks of cellular dysfunctions -altered neurotransmitter signaling, loss of neuronal homeostasis, oxidative stress, microglial activation, synaptic deficits- are at play in other neurodegenerative diseases (155). Dissecting the molecular pathways sustaining prion-induced neurotoxicity may thus have implications for amyloid- and aging-associated brain disorders.
9. ACKNOWLEDGEMENTS
We gratefully acknowledge the Groupement d'intérêt scientifique � Infections à Prions �, the French Research National Agency (ANR), the � Agence pour la Recherche sur le Cancer � (ARC) and the � Fondation pour la Recherche Médicale � (FRM) for supporting our work on prion biology and for funding Ph.D students.
10. REFERENCES
1. A. Aguzzi,A. M. Calella: Prions: protein aggregation and infectious diseases. Physiol Rev. 89, 1105-1152 (2009)
2. R. Linden, V. R. Martins, M. A. Prado, M. Cammarota, I. Izquierdo, R. R. Brentani: Physiology of the prion protein. Physiol Rev. 88, 673-728 (2008)
doi:10.1152/physrev.00007.2007
3. M. Ermonval, S. Mouillet-Richard, P. Codogno, O. Kellermann, J. Botti: Evolving views in prion glycosylation: functional and pathological implications. Biochimie 85, 33-45 (2003)
doi:10.1016/S0300-9084(03)00040-3
4. I. Laffont-Proust, B. A. Faucheux, R. Hassig, V. Sazdovitch, S. Simon, J. Grassi, J. J. Hauw, K. L. Moya, S. Haik: The N-terminal cleavage of cellular prion protein in the human brain. FEBS Lett. 579, 6333-6337 (2005)
5. V. Beringue, G. Mallinson, M. Kaisar, M. Tayebi, Z. Sattar, G. Jackson, D. Anstee, J. Collinge, S. Hawke: Regional heterogeneity of cellular prion protein isoforms in the mouse brain. Brain 126, 2065-2073 (2003)
6. A. D. Steele, S. Lindquist, A. Aguzzi: The prion protein knockout mouse: a phenotype under challenge. Prion. 1, 83-93 (2007)
doi:10.4161/pri.1.2.4346
7. N. F. McLennan, P. M. Brennan, A. McNeill, I. Davies, A. Fotheringham, K. A. Rennison, D. Ritchie, F. Brannan, M. W. Head, J. W. Ironside, A. Williams, J. E. Bell: Prion protein accumulation and neuroprotection in hypoxic brain damage. Am J Pathol. 165, 227-235 (2004)
8. J. Weise, R. Sandau, S. Schwarting, O. Crome, A. Wrede, W. Schulz-Schaeffer, I. Zerr, M. Bahr: Deletion of cellular prion protein results in reduced Akt activation, enhanced postischemic caspase-3 activation, and exacerbation of ischemic brain injury. Stroke. 37, 1296-1300 (2006)
9. A. Rangel, F. Burgaya, R. Gavin, E. Soriano, A. Aguzzi, J. A. Del Rio: Enhanced susceptibility of Prnp-deficient mice to kainate-induced seizures, neuronal apoptosis, and death: Role of AMPA/kainate receptors. J Neurosci Res 12, 2741-2755 (2007)
10. J. Bremer, F. Baumann, C. Tiberi, C. Wessig, H. Fischer, P. Schwarz, A. D. Steele, K. V. Toyka, K. A. Nave, J. Weis, A. Aguzzi: Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 13, 310-318 (2010)
doi:10.1038/nn.2483
11. S. Mouillet-Richard, B. Schneider, E. Pradines, M. Pietri, M. Ermonval, J. Grassi, J. G. Richards, V. Mutel, J. M. Launay, O. Kellermann: Cellular prion protein signaling in serotonergic neuronal cells. Ann N Y Acad Sci. 1096, 106-119 (2007)
doi:10.1196/annals.1397.076
12. H. Bueler, A. Aguzzi, A. Sailer, R. A. Greiner, P. Autenried, M. Aguet, C. Weissmann: Mice devoid of PrP are resistant to scrapie. Cell 73, 1339-1347 (1993)
13. A. J. Raeber, S. Brandner, M. A. Klein, Y. Benninger, C. Musahl, R. Frigg, C. Roeckl, M. B. Fischer, C. Weissmann, A. Aguzzi: Transgenic and knockout mice in research on prion diseases. Brain Pathol 8, 715-733 (1998)
doi:10.1111/j.1750-3639.1998.tb00197.x
14. S. Brandner, A. Raeber, A. Sailer, T. Blattler, M. Fischer, C. Weissmann, A. Aguzzi: Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. Proc Natl Acad Sci U S A 93, 13148-13151 (1996)
15. G. Mallucci, A. Dickinson, J. Linehan, P. C. Klohn, S. Brandner, J. Collinge: Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871-874 (2003)
doi:10.1126/science.1090187
16. B. Chesebro, M. Trifilo, R. Race, K. Meade-White, C. Teng, R. LaCasse, L. Raymond, C. Favara, G. Baron, S. Priola, B. Caughey, E. Masliah, M. Oldstone: Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308, 1435-1439 (2005)
17. D. A. Harris, H. L. True: New insights into prion structure and toxicity. Neuron. 50, 353-357 (2006)
doi:10.1016/j.neuron.2006.04.020
18. D. A. Harris, A. Gorodinsky, S. Lehmann, K. Moulder, S. L. Shyng: Cell biology of the prion protein. Curr Top Microbiol Immunol 207, 77-93 (1996)
19. R. Rieger, F. Edenhofer, C. I. Lasmezas, S. Weiss: The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 3, 1383-1388 (1997)
20. C. Spielhaupter, H. M. Schatzl: PrPC directly interacts with proteins involved in signaling pathways. J Biol Chem. 276, 44604-44612 (2001)
21. G. Schmitt-Ulms, G. Legname, M. A. Baldwin, H. L. Ball, N. Bradon, P. J. Bosque, K. L. Crossin, G. M. Edelman, S. J. DeArmond, F. E. Cohen, S. B. Prusiner: Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J Mol Biol 314, 1209-1225 (2001)
22. G. Schmitt-Ulms, K. Hansen, J. Liu, C. Cowdrey, J. Yang, S. J. DeArmond, F. E. Cohen, S. B. Prusiner, M. A. Baldwin: Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues. Nat Biotechnol. 22, 724-731 (2004)
doi:10.1038/nbt969
23. E. Graner, A. F. Mercadante, S. M. Zanata, O. V. Forlenza, A. L. Cabral, S. S. Veiga, M. A. Juliano, R. Roesler, R. Walz, A. Minetti, I. Izquierdo, V. R. Martins, R. R. Brentani: Cellular prion protein binds laminin and mediates neuritogenesis. Brain Res Mol Brain Res 76, 85-92 (2000)
doi:10.1016/S0169-328X(99)00334-4
24. S. Mouillet-Richard, M. Ermonval, C. Chebassier, J. L. Laplanche, S. Lehmann, J. M. Launay, O. Kellermann: Signal transduction through prion protein. Science 289, 1925-1928 (2000)
25. G. I. Keshet, O. Bar-Peled, D. Yaffe, U. Nudel and R. Gabizon: The cellular prion protein colocalizes with the dystroglycan complex in the brain. J Neurochem 75, 1889-1897 (2000)
26. M. Ermonval, A. Baudry, F. Baychelier, E. Pradines, M. Pietri, K. Oda, B. Schneider, S. Mouillet-Richard, J. M. Launay, O. Kellermann: The cellular prion protein interacts with the tissue non-specific alkaline phosphatase in membrane microdomains of bioaminergic neuronal cells. PLoS One. 4, e6497 (2009)
27. V. R. Martins, E. Graner, J. Garcia-Abreu, S. J. de Souza, A. F. Mercadante, S. S. Veiga, S. M. Zanata, V. M. Neto, R. R. Brentani: Complementary hydropathy identifies a cellular prion protein receptor. Nat Med 3, 1376-1382 (1997)
28. J. Satoh, S. Obayashi, T. Misawa, K. Sumiyoshi, K. Oosumi, H. Tabunoki: Protein microarray analysis identifies human cellular prion protein interactors. Neuropathol Appl Neurobiol. 35, 16-35 (2009)
doi:10.1111/j.1365-2990.2008.00947.x
29. D. Rutishauser, K. D. Mertz, R. Moos, E. Brunner, T. Rulicke, A. M. Calella, A. Aguzzi: The comprehensive native interactome of a fully functional tagged prion protein. PLoS One. 4, e4446 (2009)
30. J. C. Watts, H. Huo, Y. Bai, S. Ehsani, A. H. Jeon, T. Shi, N. Daude, A. Lau, R. Young, L. Xu, G. A. Carlson, D. Williams, D. Westaway, G. Schmitt-Ulms: Interactome analyses identify ties of PrP and its mammalian paralogs to oligomannosidic N-glycans and endoplasmic reticulum-derived chaperones. PLoS Pathog. 5, e1000608 (2009)
31. J. Lauren, D. A. Gimbel, H. B. Nygaard, J. W. Gilbert, S. M. Strittmatter: Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 457, 1128-1132 (2009)
32. E. Graner, A. F. Mercadante, S. M. Zanata, V. R. Martins, D. G. Jay, R. R. Brentani: Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett 482, 257-260 (2000)
doi:10.1016/S0014-5793(00)02070-6
33. A. S. Coitinho, A. R. Freitas, M. H. Lopes, G. N. Hajj, R. Roesler, R. Walz, J. I. Rossato, M. Cammarota, I. Izquierdo, V. R. Martins, R. R. Brentani: The interaction between prion protein and laminin modulates memory consolidation. Eur J Neurosci. 24, 3255-3264 (2006)
34. M. Cavaldesi, G. Macchia, S. Barca, P. Defilippi, G. Tarone, T. C. Petrucci: Association of the dystroglycan complex isolated from bovine brain synaptosomes with proteins involved in signal transduction. J Neurochem. 72, 1648-1655 (1999)
35. G. N. Hajj, M. H. Lopes, A. F. Mercadante, S. S. Veiga, R. B. da Silveira, T. G. Santos, K. C. Ribeiro, M. A. Juliano, S. G. Jacchieri, S. M. Zanata, V. R. Martins: Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins. J Cell Sci. 120, 1915-1926 (2007)
36. A. Santuccione, V. Sytnyk, I. Leshchyns'ka, M. Schachner: Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J Cell Biol 169, 341-354 (2005)
doi:10.1083/jcb.200409127
37. S. Gauczynski, J. M. Peyrin, S. Haik, C. Leucht, C. Hundt, R. Rieger, S. Krasemann, J. P. Deslys, D. Dormont, C. I. Lasmezas, S. Weiss: The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J 20, 5863-5875 (2001)
38. V. Mbazima, B. Da Costa Dias, A. Omar, K. Jovanovic, S. Weiss: Interactions between PrPc and other ligands with the 37-kDa/67-kDa laminin receptor. Front Biosci. 15, 1150-1163 (2010)
39. D. R. Taylor, N. M. Hooper: The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein. Biochem J. 402, 17-23 (2007)
doi:10.1042/BJ20061736
40. C. J. Parkyn, E. G. Vermeulen, R. C. Mootoosamy, C. Sunyach, C. Jacobsen, C. Oxvig, S. Moestrup, Q. Liu, G. Bu, A. Jen, R. J. Morris: LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein. J Cell Sci. 121, 773-783 (2008)
doi:10.1242/jcs.021816
41. A. Jen, C. J. Parkyn, R. C. Mootoosamy, M. J. Ford, A. Warley, Q. Liu, G. Bu, I. V. Baskakov, S. Moestrup, L. McGuinness, N. Emptage, R. J. Morris: Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4. J Cell Sci. 123, 246-255 (2010)
doi:10.1242/jcs.058099
42. F. Cheng, J. Lindqvist, C. L. Haigh, D. R. Brown, K. Mani: Copper-dependent co-internalization of the prion protein and glypican-1. J Neurochem. 98, 1445-1457 (2006)
43. D. R. Taylor, I. J. Whitehouse, N. M. Hooper: Glypican-1 mediates both prion protein lipid raft association and disease isoform formation. PLoS Pathog. 5, e1000666 (2009)
44. C. Hundt, S. Gauczynski, C. Leucht, M. L. Riley, S. Weiss: Intra- and interspecies interactions between prion proteins and effects of mutations and polymorphisms. Biol Chem. 384, 791-803 (2003)
doi:10.1515/BC.2003.088
45. S. Chen, A. Mange, L. Dong, S. Lehmann, M. Schachner: Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. Mol Cell Neurosci 22, 227-233 (2003)
doi:10.1016/S1044-7431(02)00014-3
46. J. Kanaani, S. B. Prusiner, J. Diacovo, S. Baekkeskov, G. Legname: Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro. J Neurochem 95, 1373-1386 (2005)
47. F. R. Lima, C. P. Arantes, A. G. Muras, R. Nomizo, R. R. Brentani, V. R. Martins: Cellular prion protein expression in astrocytes modulates neuronal survival and differentiation. J Neurochem. 103, 2164-2176 (2007)
48. V. R. Martins, F. H. Beraldo, G. N. Hajj, M. H. Lopes, K. S. Lee, M. M. Prado, R. Linden: Prion Protein: Orchestrating Neurotrophic Activities. Curr Issues Mol Biol. 12, 63-86 (2009)
49. C. Balducci, M. Beeg, M. Stravalaci, A. Bastone, A. Sclip, E. Biasini, L. Tapella, L. Colombo, C. Manzoni, T. Borsello, R. Chiesa, M. Gobbi, M. Salmona, G. Forloni: Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A 107, 2295-2300 (2010)
50. G. Schmitt-Ulms, S. Ehsani, J. C. Watts, D. Westaway, H. Wille: Evolutionary descent of prion genes from the ZIP family of metal ion transporters. PLoS One. 4, e7208 (2009)
51. C. L. Haigh, S. Y. Marom, S. J. Collins: Copper, constitutive endoproteolytic processing of the prion protein and cell signalling. Front Biosci. 15, 1086-1104 (2010)
52. M. D. Costa, K. S. Paludo, G. Klassen, M. H. Lopes, A. F. Mercadante, V. R. Martins, A. A. Camargo, L. S. Nakao, S. M. Zanata: Characterization of a specific interaction between ADAM23 and cellular prion protein. Neurosci Lett. 461, 16-20 (2009)
doi:10.1016/j.neulet.2009.05.049
53. A. Sakudo, T. Onodera, Y. Suganuma, T. Kobayashi, K. Saeki, K. Ikuta: Recent advances in clarifying prion protein functions using knockout mice and derived cell lines. Mini Rev Med Chem. 6, 589-601 (2006)
doi:10.2174/138955706776876159
54. N. Vassallo, J. Herms, C. Behrens, B. Krebs, K. Saeki, T. Onodera, O. Windl, H. A. Kretzschmar: Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival. Biochem Biophys Res Commun. 332, 75-82 (2005)
doi:10.1016/j.bbrc.2005.04.099
55. R. Schmalzbauer, S. Eigenbrod, S. Winoto-Morbach, W. Xiang, S. Schutze, U. Bertsch, H. A. Kretzschmar: Evidence for an association of prion protein and sphingolipid-mediated signaling. J Neurochem. 106, 1459-1470 (2008)
56. E. Malaga-Trillo, G. P. Solis, Y. Schrock, C. Geiss, L. Luncz, V. Thomanetz, C. A. Stuermer: Regulation of embryonic cell adhesion by the prion protein. PLoS Biol. 7, e55 (2009)
57. G. P. Solis, E. Malaga-Trillo, H. Plattner, C. A. Stuermer: Cellular functions of the prion protein: recruitment of multiprotein complexes and association with reggie/flottilin microdomains. Front Biosci. 15, 1075-1085 (2010)
58. C. A. Stuermer, M. F. Langhorst, M. F. Wiechers, D. F. Legler, S. H. Von Hanwehr, A. H. Guse, H. Plattner: PrPc capping in T cells promotes its association with the lipid raft proteins reggie-1 and reggie-2 and leads to signal transduction. FASEB J 18, 1731-1733 (2004)
59. A. S. Rambold, V. Muller, U. Ron, N. Ben-Tal, K. F. Winklhofer, J. Tatzelt: Stress-protective signalling of prion protein is corrupted by scrapie prions. Embo J. 27, 1974-1984 (2008)
60. V. Lewis, N. M. Hooper: The role of lipid rafts in prion protein biology. Front Biosci. in press (2010)
doi:10.1111/j.1471-4159.2010.06936.x
61. S. Mouillet-Richard, V. Mutel, S. Loric, C. Tournois, J. M. Launay, O. Kellermann: Regulation by neurotransmitter receptors of serotonergic or catecholaminergic neuronal cell differentiation. J Biol Chem 275, 9186-9192 (2000)
62. S. Mouillet-Richard, I. Laurendeau, M. Vidaud, O. Kellermann, J. L. Laplanche: Prion protein and neuronal differentiation: quantitative analysis of prnp gene expression in a murine inducible neuroectodermal progenitor. Microbes Infect 1, 969-976 (1999)
doi:10.1016/S1286-4579(99)80514-0
63. B. Schneider, V. Mutel, M. Pietri, M. Ermonval, S. Mouillet-Richard, O. Kellermann: NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A 100, 13326-13331 (2003)
64. K. Bedard, K. H. Krause: The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 87, 245-313 (2007)
doi:10.1152/physrev.00044.2005
65. C. C. Winterbourn: Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol. 4, 278-286 (2008)
doi:10.1038/nchembio.85
66. E. Pradines, D. Loubet, S. Mouillet-Richard, P. Manivet, J. M. Launay, O. Kellermann, B. Schneider: Cellular prion protein coupling to TACE-dependent TNF-alpha shedding controls neurotransmitter catabolism in neuronal cells. J Neurochem. 110, 912-923 (2009)
doi:10.1111/j.1471-4159.2009.06176.x
67. M. Toni, E. Spisni, C. Griffoni, S. Santi, M. Riccio, P. Lenaz, V. Tomasi: Cellular prion protein and caveolin-1 interaction in a neuronal cell line precedes fyn/erk 1/2 signal transduction. J Biomed Biotechnol. 2006, 69469 (2006)
68. C. Monnet, J. Gavard, R. M. Mege, A. Sobel: Clustering of cellular prion protein induces ERK1/2 and stathmin phosphorylation in GT1-7 neuronal cells. FEBS Lett 576, 114-118 (2004)
doi:10.1016/j.febslet.2004.08.076
69. F. A. Caetano, M. H. Lopes, G. N. Hajj, C. F. Machado, C. Pinto Arantes, A. C. Magalhaes, P. Vieira Mde, T. A. Americo, A. R. Massensini, S. A. Priola, I. Vorberg, M. V. Gomez, R. Linden, V. F. Prado, V. R. Martins, M. A. Prado: Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1. J Neurosci. 28, 6691-6702 (2008)
70. M. Pietri, A. Caprini, S. Mouillet-Richard, E. Pradines, M. Ermonval, J. Grassi, O. Kellermann, B. Schneider: Overstimulation of PrPC signaling pathways by prion peptide 106-126 causes oxidative injury of bioaminergic neuronal cells. J Biol Chem 281, 28470-28479 (2006)
71. J. Carimalo, S. Cronier, G. Petit, J. M. Peyrin, F. Boukhtouche, N. Arbez, Y. Lemaigre-Dubreuil, B. Brugg, M. C. Miquel: Activation of the JNK-c-Jun pathway during the early phase of neuronal apoptosis induced by PrP106-126 and prion infection. Eur J Neurosci. 21, 2311-2319 (2005)
72. H. Kamata, H. Hirata: Redox regulation of cellular signalling. Cell Signal. 11, 1-14 (1999)
doi:10.1016/S0898-6568(98)00037-0
73. V. J. Thannickal, B. L. Fanburg: Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279, L1005-1028 (2000)
74. N. Agell, O. Bachs, N. Rocamora, P. Villalonga: Modulation of the Ras/Raf/MEK/ERK pathway by Ca(2+), and calmodulin. Cell Signal. 14, 649-654 (2002)
doi:10.1016/S0898-6568(02)00007-4
75. L. M. Luttrell: Composition and function of g protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J Mol Neurosci. 26, 253-264 (2005)
doi:10.1385/JMN:26:2-3:253
76. P. P. Roux, J. Blenis: ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 68, 320-344 (2004)
doi:10.1128/MMBR.68.2.320-344.2004
77. X. Roucou, A. C. Leblanc: Cellular prion protein neuroprotective function: implications in prion diseases. J Mol Med 83, 3-11 (2005)
doi:10.1007/s00109-004-0605-5
78. A. J. Shaywitz, M. E. Greenberg: CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 68, 821-861 (1999)
doi:10.1146/annurev.biochem.68.1.821
79. B. Mayr, M. Montminy: Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2, 599-609 (2001)
doi:10.1038/35085068
80. E. Pradines, D. Loubet, B. Schneider, J. M. Launay, O. Kellermann, S. Mouillet-Richard: CREB-dependent gene regulation by prion protein: impact on MMP-9 and beta-dystroglycan. Cell Signal. 20, 2050-2058 (2008)
81. A. Kolonics, A. Apati, J. Janossy, A. Brozik, R. Gati, A. Schaefer, M. Magocsi: Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. Cell Signal. 13, 743-754 (2001)
doi:10.1016/S0898-6568(01)00201-7
82. D. Jancic, M. Lopez de Armentia, L. M. Valor, R. Olivares, A. Barco: Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb Cortex. 19, 2535-2547 (2009)
83. J. Zhang, D. Zhang, J. S. McQuade, M. Behbehani, J. Z. Tsien, M. Xu: c-fos regulates neuronal excitability and survival. Nat Genet. 30, 416-420 (2002)
doi:10.1038/ng859
84. G. M. Thomas, R. L. Huganir: MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. 5, 173-183 (2004)
doi:10.1038/nrn1346
85. K. Rodolfo, R. Hassig, K. L. Moya, Y. Frobert, J. Grassi, L. Di Giamberardino: A novel cellular prion protein isoform present in rapid anterograde axonal transport. Neuroreport 10, 3639-3644 (1999)
86. M. Ermonval, D. Petit, A. Le Duc, O. Kellermann, P. F. Gallet: Glycosylation-related genes are variably expressed depending on the differentiation state of a bioaminergic neuronal cell line: implication for the cellular prion protein. Glycoconj J. 26, 477-493 (2009)
doi:10.1007/s10719-008-9198-5
87. D. Shmerling, I. Hegyi, M. Fischer, T. Blattler, S. Brandner, J. Gotz, T. Rulicke, E. Flechsig, A. Cozzio, C. von Mering, C. Hangartner, A. Aguzzi, C. Weissmann: Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93, 203-214 (1998)
doi:10.1016/S0092-8674(00)81572-X
88. G. Mitteregger, M. Vosko, B. Krebs, W. Xiang, V. Kohlmannsperger, S. Nolting, G. F. Hamann, H. A. Kretzschmar: The role of the octarepeat region in neuroprotective function of the cellular prion protein. Brain Pathol. 17, 174-183 (2007)
doi:10.1111/j.1750-3639.2007.00061.x
89. L. Solforosi, J. R. Criado, D. B. McGavern, S. Wirz, M. Sanchez-Alavez, S. Sugama, L. A. DeGiorgio, B. T. Volpe, E. Wiseman, G. Abalos, E. Masliah, D. Gilden, M. B. Oldstone, B. Conti, R. A. Williamson: Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303, 1514-1516 (2004)
90. A. Li, P. Piccardo, S. J. Barmada, B. Ghetti, D. A. Harris: Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. Embo J. 26, 2777-2785 (2007)
91. F. Baumann, M. Tolnay, C. Brabeck, J. Pahnke, U. Kloz, H. H. Niemann, M. Heikenwalder, T. Rulicke, A. Burkle, A. Aguzzi: Lethal recessive myelin toxicity of prion protein lacking its central domain. Embo J. 26, 538-547 (2007)
doi:10.1038/sj.emboj.7601510
92. T. Golub, S. Wacha, P. Caroni: Spatial and temporal control of signaling through lipid rafts. Curr Opin Neurobiol. 14, 542-550 (2004)
doi:10.1016/j.conb.2004.08.003
93. K. Simons, D. Toomre: Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 1, 31-39 (2000)
doi:10.1038/35036052
94. R. G. Parton, K. Simons: The multiple faces of caveolae. Nat Rev Mol Cell Biol. 8, 185-194 (2007)
doi:10.1038/nrm2122
95. I. M. Ethell, D. W. Ethell: Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res. 85, 2813-2823 (2007)
96. P. Michaluk, L. Kolodziej, B. Mioduszewska, G. M. Wilczynski, J. Dzwonek, J. Jaworski, D. C. Gorecki, O. P. Ottersen, L. Kaczmarek: Beta-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity. J Biol Chem. 282, 16036-16041 (2007)
97. H. Yamada, F. Saito, H. Fukuta-Ohi, D. Zhong, A. Hase, K. Arai, A. Okuyama, R. Maekawa, T. Shimizu, K. Matsumura: Processing of beta-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex. Hum Mol Genet. 10, 1563-1569 (2001)
98. Y. Gasche, P. M. Soccal, M. Kanemitsu, J. C. Copin: Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain. Front Biosci. 11, 1289-1301 (2006)
99. M. Asahi, K. Asahi, J. C. Jung, G. J. del Zoppo, M. E. Fini, E. H. Lo: Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 20, 1681-1689 (2000)
100. K. Kitagawa: CREB and cAMP response element-mediated gene expression in the ischemic brain. Febs J. 274, 3210-3217 (2007)
101. Z. Zhang, P. Oliver, J. J. Lancaster, P. O. Schwarzenberger, M. S. Joshi, J. Cork, J. K. Kolls: Reactive oxygen species mediate tumor necrosis factor alpha-converting, enzyme-dependent ectodomain shedding induced by phorbol myristate acetate. Faseb J. 15, 303-305 (2001)
102. J. Szelenyi: Cytokines and the central nervous system. Brain Res Bull. 54, 329-338 (2001)
103. A. D. Kraft, C. A. McPherson, G. J. Harry: Heterogeneity of microglia and TNF signaling as determinants for neuronal death or survival. Neurotoxicology. 30, 785-793 (2009)
doi:10.1016/j.neuro.2009.07.001
104. S. Schutze, V. Tchikov, W. Schneider-Brachert: Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nat Rev Mol Cell Biol. 9, 655-662 (2008)
105. S. Haider, S. Khaliq, S. P. Ahmed, D. J. Haleem: Long-term tryptophan administration enhances cognitive performance and increases 5HT metabolism in the hippocampus of female rats. Amino Acids. 31, 421-425 (2006)
doi:10.1007/s00726-005-0310-x
106. S. Haider, S. Khaliq, D. J. Haleem: Enhanced serotonergic neurotransmission in the hippocampus following tryptophan administration improves learning acquisition and memory consolidation in rats. Pharmacol Rep. 59, 53-57 (2007)
107. K. Kobayashi, T. Kobayashi: Genetic evidence for noradrenergic control of long-term memory consolidation. Brain Dev. 23, S16-23 (2001)
doi:10.1016/S0387-7604(01)00329-1
108. A. S. Coitinho, M. H. Lopes, G. N. Hajj, J. I. Rossato, A. R. Freitas, C. C. Castro, M. Cammarota, R. R. Brentani, I. Izquierdo, V. R. Martins: Short-term memory formation and long-term memory consolidation are enhanced by cellular prion association to stress-inducible protein 1. Neurobiol Dis. 26, 282-290 (2007)
doi:10.1016/j.nbd.2007.01.005
109. D. Stenberg: Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci. 64, 1187-1204 (2007)
110. C. Vidal, C. Herzog, A. M. Haeberle, C. Bombarde, M. C. Miquel, J. Carimalo, J. M. Launay, S. Mouillet-Richard, C. Lasmezas, D. Dormont, O. Kellermann, Y. Bailly: Early dysfunction of central 5-HT system in a murine model of bovine spongiform encephalopathy. Neuroscience. 160, 731-743 (2009)
doi:10.1016/j.neuroscience.2009.02.072
111. C. Fonta, L. Negyessy, L. Renaud, P. Barone: Areal and subcellular localization of the ubiquitous alkaline phosphatase in the primate cerebral cortex: evidence for a role in neurotransmission. Cereb Cortex. 14, 595-609 (2004)
doi:10.1093/cercor/bhh021
112. M. V. Guillot-Sestier, C. Sunyach, C. Druon, S. Scarzello, F. Checler: The alpha-secretase-derived N-terminal product of cellular prion, N1, displays neuroprotective function in vitro and in vivo. J Biol Chem. 284, 35973-35986 (2009)
113. J. Weise, T. R. Doeppner, T. Muller, A. Wrede, W. Schulz-Schaeffer, I. Zerr, O. W. Witte, M. Bahr: Overexpression of cellular prion protein alters postischemic Erk1/2 phosphorylation but not Akt phosphorylation and protects against focal cerebral ischemia. Restor Neurol Neurosci. 26, 57-64 (2008)
114. N. Vassallo, J. Herms: Cellular prion protein function in copper homeostasis and redox signalling at the synapse. J Neurochem 86, 538-544 (2003)
doi:10.1046/j.1471-4159.2003.01882.x
115. B. Krebs, A. Wiebelitz, B. Balitzki-Korte, N. Vassallo, S. Paluch, G. Mitteregger, T. Onodera, H. A. Kretzschmar, J. Herms: Cellular prion protein modulates the intracellular calcium response to hydrogen peroxide. J Neurochem. 100, 358-367 (2007)
doi:10.1111/j.1471-4159.2006.04256.x
116. M. Fuhrmann, T. Bittner, G. Mitteregger, N. Haider, S. Moosmang, H. Kretzschmar, J. Herms: Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons. J Neurochem. 98, 1876-1885 (2006)
117. M. J. Berridge, P. Lipp, M. D. Bootman: The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 1, 11-21 (2000)
doi:10.1038/35036035
118. J. A. Allen, R. A. Halverson-Tamboli, M. M. Rasenick: Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci. 8, 128-140 (2007)
119. S. Mouillet-Richard, M. Pietri, B. Schneider, C. Vidal, V. Mutel, J. M. Launay, O. Kellermann: Modulation of Serotonergic Receptor Signaling and Cross-talk by Prion Protein. J Biol Chem 280, 4592-4601 (2005)
120. A. Thathiah, B. De Strooper: G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease. Sci Signal. 2, re8 (2009)
doi:10.1126/scisignal.293re8
121. Y. Sari: Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev. 28, 565-582 (2004)
doi:10.1016/j.neubiorev.2004.08.008
122. A. Bhatnagar, D. J. Sheffler, W. K. Kroeze, B. Compton-Toth, B. L. Roth: Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors. J Biol Chem. 279, 34614-34623 (2004)
123. P. Oh, J. E. Schnitzer: Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default. Mol Biol Cell 12, 685-698 (2001)
124. P. Penela, C. Ribas, F. Mayor, Jr.: Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal 15, 973-981 (2003)
doi:10.1016/S0898-6568(03)00099-8
125. S. S. Ferguson: Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53, 1-24 (2001)
-
126. A. Sakudo, K. Ikuta: Prion protein functions and dysfunction in prion diseases. Curr Med Chem. 16, 380-389 (2009)
doi:10.2174/092986709787002673
127. A. Jimenez-Huete, P. M. Lievens, R. Vidal, P. Piccardo, B. Ghetti, F. Tagliavini, B. Frangione, F. Prelli: Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. Am J Pathol. 153, 1561-1572 (1998)
128. C. Hetz, K. Maundrell, C. Soto: Is loss of function of the prion protein the cause of prion disorders? Trends Mol Med. 9, 237-243 (2003)
doi:10.1016/S1471-4914(03)00069-8
129. R. Chiesa, P. Piccardo, E. Biasini, B. Ghetti, D. A. Harris: Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities. J Neurosci. 28, 13258-13267 (2008)
130. C. Bate, M. Salmona, L. Diomede, A. Williams: Squalestatin cures prion-infected neurons and protects against prion neurotoxicity. J Biol Chem. 279, 14983-14990 (2004)
131. C. Bate, A. Williams: Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions. J Gen Virol. 85, 3797-3804 (2004)
132. D. Hwang, I. Y. Lee, H. Yoo, N. Gehlenborg, J. H. Cho, B. Petritis, D. Baxter, R. Pitstick, R. Young, D. Spicer, N. D. Price, J. G. Hohmann, S. J. Dearmond, G. A. Carlson, L. E. Hood: A systems approach to prion disease. Mol Syst Biol. 5, 252 (2009)
doi:10.1038/msb.2009.10
133. R. R. Nixon: Prion-associated increases in Src-family kinases. J Biol Chem. 280, 2455-2462 (2005)
134. R. A. LaCasse, J. F. Striebel, C. Favara, L. Kercher, B. Chesebro: Role of Erk1/2 activation in prion disease pathogenesis: absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression. J Neuroimmunol. 196, 16-26 (2008)
doi:10.1016/j.jneuroim.2008.02.009
135. R. Pamplona, A. Naudi, R. Gavin, M. A. Pastrana, G. Sajnani, E. V. Ilieva, J. A. Del Rio, M. Portero-Otin, I. Ferrer, J. R. Requena: Increased oxidation, glycoxidation, and lipoxidation of brain proteins in prion disease. Free Radic Biol Med. 45, 1159-1166 (2008)
136. S. W. Yun, M. Gerlach, P. Riederer, M. A. Klein: Oxidative stress in the brain at early preclinical stages of mouse scrapie. Exp Neurol. 201, 90-98 (2006)
doi:10.1016/j.expneurol.2006.03.025
137. M. Guentchev, S. L. Siedlak, C. Jarius, F. Tagliavini, R. J. Castellani, G. Perry, M. A. Smith, H. Budka: Oxidative damage to nucleic acids in human prion disease. Neurobiol Dis. 9, 275-281 (2002)
doi:10.1006/nbdi.2002.0477
138. M. Freixes, A. Rodriguez, E. Dalfo, I. Ferrer: Oxidation, glycoxidation, lipoxidation, nitration, and responses to oxidative stress in the cerebral cortex in Creutzfeldt-Jakob disease. Neurobiol Aging. 27, 1807-1815 (2006)
139. J. I. Kim, W. K. Ju, J. H. Choi, E. Choi, R. I. Carp, H. M. Wisniewski, Y. S. Kim: Expression of cytokine genes and increased nuclear factor-kappa B activity in the brains of scrapie-infected mice. Brain Res Mol Brain Res. 73, 17-27 (1999)
doi:10.1016/S0169-328X(99)00229-6
140. J. K. Jin, N. H. Kim, D. S. Min, J. I. Kim, J. K. Choi, B. H. Jeong, S. I. Choi, E. K. Choi, R. I. Carp, Y. S. Kim: Increased expression of phospholipase D1 in the brains of scrapie-infected mice. J Neurochem. 92, 452-461 (2005)
doi:10.1111/j.1471-4159.2004.02881.x
141. A. Corsaro, S. Thellung, V. Villa, D. R. Principe, D. Paludi, S. Arena, E. Millo, D. Schettini, G. Damonte, A. Aceto, G. Schettini, T. Florio: Prion protein fragment 106-126 induces a p38 MAP kinase-dependent apoptosis in SH-SY5Y neuroblastoma cells independently from the amyloid fibril formation. Ann N Y Acad Sci. 1010, 610-622 (2003)
doi:10.1196/annals.1299.114
142. S. Thellung, V. Villa, A. Corsaro, S. Arena, E. Millo, G. Damonte, U. Benatti, F. Tagliavini, T. Florio, G. Schettini: p38 MAP kinase mediates the cell death induced by PrP106-126 in the SH-SY5Y neuroblastoma cells. Neurobiol Dis. 9, 69-81 (2002)
doi:10.1006/nbdi.2001.0461
143. D. Vilette: Cell models of prion infection. Vet Res. 39, 10 (2007)
144. H. M. Schatzl, L. Laszlo, D. M. Holtzman, J. Tatzelt, S. J. DeArmond, R. I. Weiner, W. C. Mobley, S. B. Prusiner: A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis. J Virol 71, 8821-8831 (1997)
145. O. Milhavet, H. E. McMahon, W. Rachidi, N. Nishida, S. Katamine, A. Mange, M. Arlotto, D. Casanova, J. Riondel, A. Favier, S. Lehmann: Prion infection impairs the cellular response to oxidative stress. Proc Natl Acad Sci U S A 97, 13937-13942 (2000)
146. S. Cronier, H. Laude, J. M. Peyrin: Prions can infect primary cultured neuronAs and astrocytes and promote neuronal cell death. Proc Natl Acad Sci U S A 101, 12271-12276 (2004)
147. R. K. Giri, R. Young, R. Pitstick, S. J. DeArmond, S. B. Prusiner, G. A. Carlson: Prion infection of mouse neurospheres. Proc Natl Acad Sci U S A 103, 3875-3880 (2006)
148. O. Milhavet, D. Casanova, N. Chevallier, R. D. McKay, S. Lehmann: Neural stem cell model for prion propagation. Stem Cells 10, 2284-2291 (2006)
149. M. E. Herva, A. Relano-Gines, A. Villa, J. M. Torres: Prion infection of differentiated neurospheres. J Neurosci Methods 2010, 3 (2010)
doi:10.1016/j.jneumeth.2010.02.022
150. S. Mouillet-Richard, N. Nishida, E. Pradines, H. Laude, B. Schneider, C. Feraudet, J. Grassi, J. M. Launay, S. Lehmann, O. Kellermann: Prions impair bioaminergic functions through serotonin- or catecholamine-derived neurotoxins in neuronal cells. J Biol Chem. 283, 23782-23790 (2008)
151. J. M. Ledoux: Effects on the serotoninergic system in sub-acute transmissible spongiform encephalopathies: current data, hypotheses, suggestions for experimentation. Med Hypotheses 64, 910-918 (2005)
doi:10.1016/j.mehy.2004.11.020
152. A. C. Magalhaes, G. S. Baron, K. S. Lee, O. Steele-Mortimer, D. Dorward, M. A. Prado, B. Caughey: Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J Neurosci. 25, 5207-5216 (2005)
153. G. G. Kovacs, H. Budka: Prion diseases: from protein to cell pathology. Am J Pathol. 172, 555-565 (2008)
doi:10.2353/ajpath.2008.070442
154. G. Tamguney, K. Giles, D. V. Glidden, P. Lessard, H. Wille, P. Tremblay, D. F. Groth, F. Yehiely, C. Korth, R. C. Moore, J. Tatzelt, E. Rubinstein, C. Boucheix, X. Yang, P. Stanley, M. P. Lisanti, R. A. Dwek, P. M. Rudd, J. Moskovitz, C. J. Epstein, T. D. Cruz, W. A. Kuziel, N. Maeda, J. Sap, K. H. Ashe, G. A. Carlson, I. Tesseur, T. Wyss-Coray, L. Mucke, K. H. Weisgraber, R. W. Mahley, F. E. Cohen, S. B. Prusiner: Genes contributing to prion pathogenesis. J Gen Virol. 89, 1777-1788 (2008)
155. J. J. Palop, J. Chin, L. Mucke: A network dysfunction perspective on neurodegenerative diseases. Nature. 443, 768-773 (2006)
doi:10.1038/nature05289
155.J. J. Palop, J. Chin, L. Mucke: A network dysfunction perspective on neurodegenerative diseases. Nature. 443, 768-773 (2006) DOI: http://dx.doi.org/10.1038/nature05289
Abbreviations: CREB : cAMP-responsive element binding protein, ERK1/2 : extracellular-regulated kinases 1 and 2, GPCR : G-protein coupled receptor, MAPK : mitogen activated protein kinase, NADPH oxidase : nicotinamide adenine dinucleotide phosphate-dependent oxidase, NE :norepinephrine, PI3K : phosphatidylinositol 3 kinase, PKC : protein kinase C, PrP : prion protein, PrPC : cellular prion protein, PrPSc : scrapie prion protein, ROS : reactive oxygen species, TACE : TNF-alpha Converting Enzyme, TNF-alpha : Tumor Necrosis Factor-alpha, 5-HT : 5-hydroxytryptamine.
Key Words: Prion, Signaling, Infection, Neuron, Review
Send correspondence to: Sophie Mouillet-Richard, INSERM U747, Paris Descartes University, 45 rue des Saints Peres, 75006 Paris, France, Tel: 33-1-4286- 2067 Fax: 33-1-4286-4068, E-mail:sophie.mouillet-richard@parisdescartes.fr