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British Medical Bulletin 66:61-70 (2003)
© 2003 The British Council

Putative functions of PrPC

Corinne Ida Lasmézas

Laboratory for Prion Pathogenesis, Service de Neurovirologie, Commissariat à l’Energie Atomique, Fontenay-aux-Roses, France


   Abstract
Top
 Abstract
Introduction
 Cellular localisation of PrPC
 PrPC interacting molecules
 Synaptic function
 Copper binding: transport,...
 Signalling
 References
 
While the exact function of the cellular prion protein (PrPC) remains unknown, there are several leads due to increasing knowledge on the localisation and interaction of PrPC with other molecules. This chapter will concentrate on these aspects. Identified ligands of PrPC mainly belong to the categories of heat-shock proteins, membrane-bound receptors, or heparan sulphates. The possible synaptic role of PrPC has been exemplified by electrophysiological findings in PrPo/o mice and the studies of PrPC as a copper-binding molecule that could regulate the copper content of the synaptic cleft. The latter property of PrPC may also endow PrPC with the activity of a copper-dependent superoxide dismutase. Binding of PrPC to signalling molecules suggests a role as a transmitter of information from the extracellular milieu to the cell and a trigger for a molecular cascade. This agrees with new data on PrPC receptors and the role of PrPC in cell survival.


   Introduction
Top
 Abstract
 Introduction
Cellular localisation of PrPC
 PrPC interacting molecules
 Synaptic function
 Copper binding: transport,...
 Signalling
 References
 
It is still early days in understanding the function of the cellular form of the prion protein, called PrPC (as opposed to the disease-related form PrPSc or PrPres). Much hope was pinned on the use of PrPC knock-out mice to unveil the function of the protein, but instead no obvious phenotype was observed1. Indeed, it is part of the prion enigma that a protein expressed at high levels in the brain, where the expression is regulated during development and is also found in most body tissues, appears to be dispensable. The proposed functions for this ubiquitous protein range from a role as a metal ion binding protein which would regulate the copper concentration in synaptic regions of the neuron to a universally vital role, the latter being currently understood in such a contradictory way that is being referred to as promoting either cell death or survival. Between these two extremes, a variety of other roles or variations thereof have been proposed, sometimes in variably close relation to experimental data. In this context, writing a review of current knowledge of the role of PrPC as a cellular protein appears to be a rather delicate task. One way to approach the role of a protein is to look at the other molecules that could be part of the functional cascade. Thus, this chapter will concentrate mainly on the putative functions of PrPC that can be derived from its localisation and the newly accumulated data on its interaction with cellular partners.


   Cellular localisation of PrPC
Top
 Abstract
 Introduction
 Cellular localisation of PrPC
PrPC interacting molecules
 Synaptic function
 Copper binding: transport,...
 Signalling
 References
 
In non-neuronal cells and in cultured cell lines, PrPC is generally found at the cell membrane associated with cholesterol-rich microdomains called rafts2. In polarized cells, like epithelial cells, PrPC is also found to be associated with detergent-resistant microdomains, but has a basolateral localization which is unusual for a GPI-anchored protein3. There are some exceptions to this plasma membrane localisation such as the stomach, where PrPC was observed in secretion granules of epithelial cells4. PrPC was also found to be localised in secretory mammary gland tissues, its expression varying with physiological state (Jeanne Grosclaude, personal communication). Interestingly, a PrPC-interacting protein, synapsin I, is abundant not only in neuronal tissues but also in other cell types involved in exocytosis, such as cells of the endocrine system5.


   PrPC interacting molecules
Top
 Abstract
 Introduction
 Cellular localisation of PrPC
 PrPC interacting molecules
Synaptic function
 Copper binding: transport,...
 Signalling
 References
 
The interest in PrPC protein ligands is not new and the description of PrPSc binding proteins goes back to 1990 with the PrPC ligands called Pli 45 and Pli 110 according to their molecular weights6. Pli 45 was identified as glial fibrillary acidic protein (GFAP), an astrocytic marker that accumulates concomitantly with disease-associated PrPC during TSEs7.

The two-hybrid system of yeast, which can be used to demonstrate the interaction between two proteins or, when used as a screen, to identify PrPC-interacting proteins from a cDNA expression library, led to the identification of the anti-apoptotic molecule Bcl-28,9, the chaperone Hsp6010, the 37-kDa laminin receptor precursor LRP11, as well as synapsin Ib, the adaptor protein Grb2 and the unknown protein Pint 1 (prion interactor 1)12.

PrPC could be immunoprecipitated with antibodies to binding proteins grp94, protein disulphide isomerase (PDI), calnexin (Clx) and calreticulin13.

It has also been shown that PrPC binds laminin in a saturable fashion and that the latter promotes neurite out-growth in PC12 cells and primary neurons of rodents14. This effect of laminin is, at least in part, mediated by PrPC as shown by Graner et al15.

In another attempt to identify a PrPC ligand, the so-called complementary hydropathy approach was used. This is based on the assumption that the cDNA complementary to that encoding the molecule of interest generates a molecule that has a hydropathy profile which is the mirror image of that of the target protein and thus binds to it. Applying this technique to the PrPC113–128 peptide, a molecule was found migrating as a doublet of 60–66 kDa after denaturing gel electrophoresis, and it bound to PrPC. It was called PrR (for prion receptor). Later, this molecule was identified as the stress-inducible protein 1 (STI-1)16. Interestingly, this molecule is a heat-shock protein which acts as a co-factor for chaperones such as HSP70 and HSP90.

Finally, there are many reports showing that heparan sulphates play a role in the life cycle of the prion protein and possibly in the pathogenesis of the disease. First, heparan sulphates interact with PrPC17–19. The main binding domain is the N-terminal region of PrPC20,21. It is not fully clear whether the extreme, highly basic N-terminus PrPC23–53 is involved22,23, or if the binding occurs at the octapeptide repeat region PrPC53–93. The latter seems relevant as copper and heparin compete for the binding to this region of PrPC19,24. Functionally, cell-surface glycosaminoglycan molecules, which are components of heparan sulphates, seem to play a role in PrPC internalisation21,23. Sulphated glycans stimulate cell-free conversion of PrPC25 and are associated with amyloid plaques or PrPSc deposits26,27 in the brain during prion diseases, pointing to a role of these molecules in the pathogenesis of these diseases.

The molecules interacting with PrPC, due to their intrinsic activity, localisation in a cell compartment and within a signalling pathway, are a major focus of study into disentangling the question of the possible role of PrPC. Most will, therefore, be mentioned in the following paragraphs.


   Synaptic function
Top
 Abstract
 Introduction
 Cellular localisation of PrPC
 PrPC interacting molecules
 Synaptic function
Copper binding: transport,...
 Signalling
 References
 
In neuronal cells, small, high-density patches of PrPC are found on the neuronal surface (particularly at the cell body of sensory neurons). These correspond to discrete sphingolipid–sterol ‘rafts’ as mentioned above28. During hamster brain development, PrPC distribution shifts from fibre tracts (which hints towards a signalling function during development) to the neuropil which in adults is rich in synapses. The appearance of a neuropil localisation was found to follow the time course of synaptogenesis in several structures29. PrPC was found in the presynaptic nerve terminals in several instances30–33.

Biochemical studies have demonstrated that PrPC is a membrane-bound protein, thus a tempting localisation would be at the plasma membrane of the synapse. However, PrPC seems also to be associated with synaptic vesicles. PrPC probably cycles between these compartments; the exact proportion of molecules present in either one remains to be determined. Interestingly, the PrPC interacting protein synapsin I is associated with small synaptic vesicles and both synapsin I and Grb2 co-purify with PrPC in neuronal microsomal vesicles12. This would suggest a role in the recycling of the vesicles or a more direct role in synaptic activity33. The latter has been substantiated by some electrophysiological studies conducted in mice devoid of PrPC. Weakened GABA-A ({gamma}-aminobutyric acid type A) receptor-mediated fast inhibition and impaired long-term potentiation were reported in PrPC knock-out mice34. In contrast, other laboratories did not report any anomalies in neuronal excitability and synaptic transmission in the hippocampus35 or cerebellar Purkinje cells36 of PrPo/o mice. Conditional knock-out mice harbour reduced after-hyperpolarization potentials in hippocampal CA1 cells, revealing that PrPC modulates neuronal excitability37, while high levels of PrPC mediate a more robust synaptic transmission in the mouse hippocampus38.

As a whole, it seems that while PrPC is not required for most vital synaptic functions, its absence results in a lack of fine tuning of neuronal functions. This is substantiated by the observation of aberrant sleep patterns39 and increased locomotor activity40 in PrPC knock-out mice.


   Copper binding: transport, carrier, enzyme?
Top
 Abstract
 Introduction
 Cellular localisation of PrPC
 PrPC interacting molecules
 Synaptic function
 Copper binding: transport,...
Signalling
 References
 
PrPC is a metal ion-binding protein as it binds copper with low micromolar affinity, highly relevant to a potentially related activity41,42. Zinc, manganese and nickel cations also bind to PrPC, but with lower affinities than does copper43–45. The binding is co-operative and occurs via histidines of the N-terminal region of PrPC. In this region, six conserved His residues have been identified (four in the octarepeats, the others at position 96 and 111) for which the Kds for copper binding are ~10–14 M45. The affinity constant is challenged by other studies which report a role for glycine and proline residues in the co-operative binding of copper46. The N-terminal part of the prion protein harbours high structural flexibility and is involved in the binding of PrPC to a number of ligands. Therefore, it is conceivable that copper binding plays a structural role or may influence the binding of PrPC to other proteins.

The fact that mice devoid of PrPC harbour 50% lower copper concentrations in synaptosomal fractions than their PrPC expressing counterparts suggests that PrPC could regulate the copper concentration in the synaptic region of the neuron. It may play a role in the re-uptake of copper into the presynaptic cell47. If PrPC plays a role in the transport of copper across the plasma membrane, it implies that PrPC interacts with a copper-scavenging protein such as metallothionein, or with copper chaperones that deliver copper to cupro-enzymes because, due to its extreme toxicity, free copper is kept at negligible concentrations in the cytoplasm (< 1 ion/cell)48. Copper added to cultured neuroblastoma cells stimulate PrPC endocytosis49. Hence, it can be hypothesized that the transport of copper from the extra- to the intracellular compartment is operated through PrPC internalisation. Alternatively, PrPC may act as a copper buffer at the synaptic cleft, capturing copper and handling it over to another membrane transporter.

Further, it can be speculated that copper, by altering the conformation of the N-terminal domain of PrPC, would enhance its affinity for a cellular PrPC-receptor. Of note, it has been shown that PrPC binds to the laminin receptor via two binding sites, one of them being located in the N-terminal octarepeat domain of PrPC50.

Alternatively, recombinant as well as immunoprecipitated murine PrPC have been shown to harbour the activity of a copper/zinc-dependent superoxide dismutase (SOD1) which endows PrPC with antioxidant activity51. Copper has to be present during PrPC folding for the protein to show SOD activity. In line with these results, the same authors report a reduced activity of cytosolic SOD1 in the brains of PrPo/o mice52 and an increased SOD1 activity and copper loading in mice that overexpress PrPC53. Moreover, SOD activity in brain lysates from wild-type mice was reduced after PrPC depletion using Sepharose beads immobilized with anti-PrPC monoclonal antibodies54. These data were contradicted by others who failed to detect significantly differing amounts of copper in subcellular fractions of brain from PrPo/o, wild-type mice and mice overexpressing 10 times PrPC as well as any effect of PrPC expression level on SOD1 activity55. These authors propose that PrPC serves as a carrier for copper ions, transferring copper to and from non-ceruloplasmin species that, like PrPC, have dissociation constants in the low micromolar range.


   Signalling
Top
 Abstract
 Introduction
 Cellular localisation of PrPC
 PrPC interacting molecules
 Synaptic function
 Copper binding: transport,...
 Signalling
References
 

Experimental clues for a signalling function
 The activation of the non-receptor tyrosine kinase fyn, which is enriched in brain synaptosomes and has been implicated in long-term potentiation56, could represent a cellular pathway through which PrPC influences synaptic function57.

PrPC interacts with Grb2 which links signals coming from extracellular and/or transmembrane receptors to intracellular signalling molecules, in the absence of intrinsic enzymatic functions58. This signalling cascade seems crucial for cell survival59. Recombinant bovine PrPC is able to interact with and increase the phosphotransferase activity of CK2 also termed casein kinase 2. CK2 is a pleiotropic protein kinase known to impinge on many proteins implicated in a variety of signal transduction pathways including cell proliferation60.

Moreover, in the neonatal hamster brain, although overall levels of PrPC were low compared to the adult, the protein was readily detectable in fibre tracts of elongating axons suggesting a signalling role during axonal growth. PrPC localization at the surface of elongating retinal axons was confirmed in explant experiments29.

Role in cell survival and differentiation
 Several experimental findings suggest that PrPC may play a major role in cell survival. PrPC can bind to the anti-apoptotic factor Bcl-28. PrPC can partially protect neuroblastic layer cells from retinal rat explants from anisomycin-induced death, probably through interaction with a cell-surface receptor (see below)16,61. Primary neurons taken from PrPo/o mice are less resistant to serum deprivation than their PrPC-expressing counterparts, but this hypersensitivity could be counteracted by overexpression of Bcl-262. Moreover, PrPC could protect human primary neurons against Bax-mediated cell death to levels equal to the neuroprotective function of Bcl-263. This neuroprotective function requires the presence of the octapeptide repeats of PrPC.

A role for PrPC in neuroprotective signalling was proposed even prior to the characterization of PrPC-receptors that may also account for this function. Indeed, mice expressing N-terminally truncated PrPC in a PrPo/o genetic background suffered from neurodegeneration, and the normal phenotype was rescued by the expression of the full-length protein64. These experiments suggested that PrPC binds to a protein involved in cell survival in a region carboxy terminal to about amino acid 121, while the aminoproximal part prior to this amino acid induces correct signal transduction.

In contrast to these findings, it has been shown that the overexpression of PrPC sensitizes cultured cells to staurosporine-induced death and increases caspase 3 activity, an enzyme involved in the apoptotic cascade65. Also, cytosolic PrPC, abnormally accumulated due to proteasome dysfunction, demonstrates enhanced protease resistance and acute toxicity66,67.

Overall, given the current state of knowledge, it seems that while the PrPC protein is involved in cell survival, any abnormal deviation from its steady-state concentration and compartmentalization in the cell leads the protein to exert adverse cytotoxic effects.

Receptors
 Recent efforts to identify PrPC-binding molecules have led to the discovery of several receptor candidates for the prion protein including the 37/67 kDa laminin receptor (LRP/LR)68 and the murine stress inducible protein I (mSTI)16. While the role(s) of these molecules in the life cycle of PrPC remains to be precisely defined, there are some experimental data on the effects of their interaction with PrPC.

It has been shown that PrPC induces a neuroprotective signal through interaction with cell surface STI 116.

LRP/LR mediates the binding and internalisation of recombinant and purified PrPC to cells in culture, suggesting a role in the endocytic pathway of the protein. LRP/LR is a protein that undergoes a complex maturation process involving acylation, phosphorylation of the 37-kDa precursor and probably heterodimerisation with an as yet unknown molecule. Consequently, several isoforms are present in the brain, as revealed by gel electrophoresis, which interact with PrPC69. The pleiomorphism of LRP/LR is accompanied by the variety of its functions and localisations. For instance, it is found abundantly in basal membranes where it plays a role in the attachment and migration of endothelial cells, but is also found on neurons and promotes neurite out-growth. It has been located on epithelial intestinal cells (J-G Fournier, personal communication and Shmakov et al70) where it probably plays a role in maintaining the integrity of the intestinal barrier. Therefore, LRP/LR might act as the cellular receptor for the recycling/catabolism of endogenous PrPC, but might also interact with PrPC molecules present at the surface of other cells, thus contributing to cell communication and survival. Finally, LRP/LR might be a receptor for PrPres, hence promoting cell-to-cell propagation of infectivity.

Cell surface glycosaminoglycans (GAGs) were also shown to bind to PrPC and promote its internalisation21,23.

As a matter of fact, heparin also binds to the 37/67-kDa laminin receptor71,72. We found that two binding sites exist on PrPC and on LRP/LR and that the interaction of these proteins is mediated/assisted by cellular HSPGs at one of these binding sites50. Therefore, our data on the role of LRP/LR as a receptor for PrPC are consistent with previous findings on the role of GAGs which are part of HSPGs. Plate VIII proposes a hypothetical LRP/LR–PrPC–HSPGs interaction complex.



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  		Plate VIII Model of the interaction of the prion protein with a cell-surface receptor, derived from the study of LRP/LR50. The interaction takes place at a binding domain located in the globular domain of PrP and at another domain located in the flexible N-terminal region of the protein, responsible for signal transduction (to account for data showing the occurrence of neuronal dysfunction in mice expressing N-terminally truncated prion proteins64). This interaction may be aided or competed for by copper ions binding to the N-terminal domain of PrP. Heparan sulphate proteoglycans (HSPGs) act as co-receptors.

 

   Footnotes
 
Correspondence to: Dr Corinne Ida Lasmézas, Laboratory for Prion Pathogenesis, Service de Neurovirologie, Commissariat à l’Energie Atomique, DSV/DRM, BP6, F-92265 Fontenay-aux-Roses cedex, France


   References
Top
 Abstract
 Introduction
 Cellular localisation of PrPC
 PrPC interacting molecules
 Synaptic function
 Copper binding: transport,...
 Signalling
 References
 

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