PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of prionLink to Publisher's site
 
Prion. 2009 Oct-Dec; 3(4): 187–189.
PMCID: PMC2807689

Role of prions in neuroprotection and neurodegeneration

A mechanism involving glutamate receptors?

Abstract

There is increasing evidence that cellular prion protein plays important roles in neurodegeneration and neuroprotection. One of the possible mechanism by which this may occur is a functional inhibition of ionotropic glutamate receptors, including N-Methyl-D-Aspartate (NMDA) receptors. Here we review recent evidence implicating a possible interplay between NMDA receptors and prions in the context of neurodegenerative disorders. Such is a functional link between NMDA receptors and normal prion protein, and therefore possibly between these receptors and pathological prion isoforms, raises interesting therapeutic possibilities for prion diseases.

Key words: NMDA, NR2D, glutamate, neuroprotection, calcium

Prions are most often discussed in the context of transmissible spongiform encephalopathies (TSEs) which encompass a range of neurological disorders that include human Creutzfeldt-Jakob disease (among others), sheep scrapie and bovine spongiform encephalopathy.1,2 It is well established that these disorders arise from a progressive conversion of the normal, mainly helical form of cellular prion protein (PrPC) into a different PrPSc protein conformation with a high beta sheet content.3 In their PrPSc form, prions act as templates that catalyze misfolding of PrPC to produce increasing levels of PrPSc, which likely represents several or even many different conformational states of the same source protein, resulting in diverse clinical phenotypes. This in turn leads to accumulation of PrPSc deposits in the brain that can appear as aggregates and amyloid-like plaques4 and which disrupt normal neurophysiology.5 While the neuropathology of TSE's has been explored in great detail dating back to the 1920s,6 less effort has perhaps been expended on understanding the cellular and physiological function of PrPC which is ubiquitously expressed, and found even in simple organisms.5,7,8 A number of mouse lines either lacking PrPC or overexpressing PrPC have been created, including the widely used Zurich I PrPC knockout strain.9,10 Despite the wide distribution of PrPC in the mammalian CNS, it perhaps surprisingly has only a relatively mild behavioral phenotype that appears to include some deficits in spatial learning at the behavioral level11,12 as well as alterations in long term potentiation at the cellular level.1317 In addition, it has been shown that these mice show an increased excitability of hippocampal neurons.13,1820 In contrast, deletion of certain parts of the PrPC protein in vivo can have serious physiological consequences. For example, deletion of a stretch of amino acids between just upstream of the octarepeat copper binding motifs produces a lethal phenotype, that can be rescued by overexpression of increasing levels of normal PrPC.21,22 Of particular note, these deletion mutants show degeneration of axons and myelin, both in the CNS and in peripheral nerves; indeed some mutants show a predilection for axomyelinic degeneration with little neuronal pathology,21 suggesting that certain mutated forms of PrP have a direct toxic effect on oligodendrocytes and/or myelin.23 Moreover, activation of the Dpl1 gene in mice lacking PrPC leads to an ataxic phenotype, that is not observed in the presence of PrPC.24 Collectively, this indicates that PrPC may act in a protective capacity and in contrast, certain abnormal forms of PrP are “toxic”, promoting much more injury to various elements of the CNS and PNS than outright absence of wild-type PrPC.

This notion is further corroborated by a number of studies in PrPC knockout mice, both in vivo and in cell culture models. Cultured hippocampal neurons from PrPC null mice display greater apoptosis during oxidative stress.25 Moreover, overexpression of PrPC in rats protects them from neuronal damage during ischemic stroke, whereas PrPC null mice show greater damage.2729 When PrPC null mice are subjected to different types of seizure paradigms, they showed increased mortality and increased numbers of seizures.30 This increased neuronal damage can be diminished by the NMDA receptor blocker MK-801,31 potentially implicating glutamate receptors in this process. Finally, it was recently shown that the absence of PrPC protein protects neurons from the deleterious effects of beta amyloid, a protein involved in Alzheimer disease.32 It is important to note that NMDA receptors have been implicated in seizure disorders and in cell death during ischemic stroke.3335 Indeed, our own work has shown that NMDA receptors expressed endogenously in myelin contribute to myelin damage and may be one of the first steps leading to demyelination.36 Furthermore, the NMDA receptor blocker memantine is used to treat Alzheimer disease, implicating NMDA receptors. The observations above suggest that there may be an interplay between NMDA receptor activity and the physiological function of PrPC. In support of this hypothesis, our recent work has directly identified a common functional and molecular link between NMDA receptors and PrPC.37 Brain slices obtained from Zurich I PrPC null mice showed an increased excitability of hippocampal slices, which could be ablated by blocking NMDA receptor activity with amino-5-phosphonovaleric acid. Removal of extracellular magnesium ions to enhance NMDA receptor activity resulted in stronger pro-excitatory effects in slices and cultured neurons from PrPC null mice compared with those from normal animals. Synaptic recordings indicate that the amplitude and duration of NMDA mediated miniature synaptic currents is increased in PrPC null mouse neurons, and evoked NMDA receptor currents show a dramatic slowing of deactivation kinetics in PrPC null mouse neurons. The NMDA current kinetics observed in these neurons were qualitatively consistent with NMDA receptors containing the NR2D subunit.38 Consistent with a possible involvement of NR2D containing receptors, siRNA knockdown of NR2D normalized current kinetics in PrP-null mouse neurons. Furthermore, a selective co-immunoprecipitation between PrPC and the NR2D, but not NR2B subunits, was observed. This then may suggest the possibility that under normal circumstances, PrPC serves to suppress NR2D function, but when PrPC is absent, NR2D containing receptors become active, and because of their slow kinetics, may contribute to calcium overload under circumstances where excessive (or even normal) levels of glutamate are present. This would include conditions such as epileptic seizures, ischemia and Alzheimer disease, thus providing a possible molecular explanation for the link between PrPC and neuroprotection under pathophysiological conditions. Indeed, NMDA promoted greater toxicity in PrPC null mouse neurons, and upon injection into brains of PrPC null mice. It is interesting to note that one of the major NMDA receptor subtypes expressed in myelin is NR2D, thus bridging the observations of Micu et al.36 of NMDA receptor mediated cell death in ischemic white matter, and those of Baumann and colleagues21 showing that PrPC deletion mutants can cause damage to myelin.

How might PrPC deletion mutants affect neuronal survival? One possibility may be that these deletion mutants compete with normal PrPC for NMDA receptors, but are unable to functionally inhibit them. Alternatively, it is possible that the PrPC deletion mutants, by virtue of binding to the receptors, may in fact increase receptor activity, thus causing increased cell death. In both cases, increasing the expression of normal PrPC would be expected to outcompete the deletion variants, thus reestablishing the protective function. A similar mechanism could perhaps apply to TSEs. It is possible that the PrPSc form, perhaps in a manner reminiscent of the PrPC deletion mutants, may be unable to inhibit NMDAR function, or perhaps would even enhance it. Any excess glutamate that may be released as a result of cell damage due to PrPSc aggregates, or even normally released amounts glutamate during the course of physiological neuronal signaling, could be sufficient to cause NMDAR mediated cell death and neuronal degeneration. In this context, it is interesting to note that chronic administration of the weakly NR2D selective inhibitor memantine delays death as a consequence of scrapie infection in mice.39 In the context of Alzheimer disease, binding of PrPC to beta amyloid may prevent the inhibitory action of PrPC on NMDA receptor function, thus increasing NMDA receptor activity and promoting cell death. This then may perhaps explain the beneficial effects of memantine in the treatment of Alzheimer disease.

In summary, despite the fact that PrPC is one of the most abundantly expressed proteins in the mammalian CNS, its physiological role is uncertain. Recent observations from our labs have established an unequivocal functional link between normal prion protein and the ubiquitous excitatory NMDA receptor. Thus, one of the key physiological roles of PrPC may be regulation of NMDA receptor activity. The presence of abnormal species of prion protein, whether acquired via “infection”, spontaneous conformational conversion or genetically inherited, may in turn alter normal function and regulation of NMDA receptors, leading to chronic “cytodegeneration” of elements in both gray and white matter regions of the CNS. This key functional link between PrP and glutamate receptors may provide our first opportunity for rational therapeutic design against the devastating spongiform encephalopathies and potentially other neurodegenerative disorders not traditionally considered as TSE's.

Acknowledgements

P.K.S. and G.W.Z. are supported through the Canada Research Chairs Program and are Scientists of the Alberta Heritage Foundation for Medical Research. G.W.Z. is a member of PrioNet Canada and funded by the Alberta Prion Research Institute.

Footnotes

References

1. DeArmond SJ, Prusiner SB. Perspectives on prion biology, prion disease pathogenesis and pharmacologic approaches to treatment. Clin Lab Med. 2003;23:1–41. [PubMed]
2. Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. Prion protein biology. Cell. 1998;93:337–348. [PubMed]
3. Moore RA, Taubner LM, Priola SA. Prion protein misfolding and disease. Curr Opin Struct Biol. 2009;19:14–22. [PMC free article] [PubMed]
4. DeArmond SJ. Discovering the mechanisms of neurodegeneration in prion diseases. Neurochem Res. 2004;29:1979–1998. [PubMed]
5. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR. Physiology of the prion protein. Physiol Rev. 2008;88:673–728. [PubMed]
6. Will RG, Alpers MP, Dormont D, Schonberger LB. Prusiner SB, editor. Infectious and Sporadic Prion Diseases. “Prion biology and diseases” 2004;13:629–672.
7. Fournier JG, Escaig-Haye F, Grigoriev V. Ultrastructural localization of prion proteins: physiological and pathological implications. Microsc Res Tech. 2000;50:76–88. [PubMed]
8. Salés N, Rodolfo K, Hässig R, Faucheux B, Di Giamberardino L, Moya KL. Cellular prion protein localization in rodent and primate brain. Eur J Neurosci. 1998;10:2464–2471. [PubMed]
9. Sakudo A, Onodera T, Suganuma Y, Kobayashi T, Saeki K, Ikuta K. Recent advances in clarifying prion protein functions using knockout mice and derived cell lines. Mini Rev Med Chem. 2006;6:589–601. [PubMed]
10. Steele AD, Lindquist S, Aguzzi A. The prion protein knockout mouse: A phenotype under challenge. Prion. 2007;1:83–93. [PMC free article] [PubMed]
11. Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. 1992;356:577–582. [PubMed]
12. Criado JR, Sanchez-Alavez M, Conti B, Giacchino JL, Wills DN, Henriksen SJ, et al. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis. 2005;19:255–265. [PubMed]
13. Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG. Prion protein is necessary for normal synaptic function. Nature. 1994;370:295–297. [PubMed]
14. Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA. Hippocampal synaptic plasticity in mice devoid of cellular prion protein. Brain Res Mol Brain Res. 2004;131:58–64. [PubMed]
15. Maglio LE, Martins VR, Izquierdo I, Ramirez OA. Role of cellular prion protein on LTP expression in aged mice. Brain Res. 2006;1097:11–18. [PubMed]
16. Manson JC, Hope J, Clarke AR, Johnston A, Black C, MacLeod N. PrP gene dosage and long term potentiation. Neurodegeneration. 1995;4:113–114. [PubMed]
17. Curtis J, Errington M, Bliss T, Voss K, MacLeod N. Age-dependent loss of PTP and LTP in the hippocampus of PrP-null mice. Neurobiol Dis. 2003;13:55–62. [PubMed]
18. Colling SB, Collinge J, Jefferys JG. Hippocampal slices from prion protein null mice: disrupted Ca(2+)-activated K+ currents. Neurosci Lett. 1996;209:49–52. [PubMed]
19. Colling SB, Khana M, Collinge J, Jefferys JG. Mossy fibre reorganization in the hippocampus of prion protein null mice. Brain Res. 1997;755:28–35. [PubMed]
20. Mallucci GR, Ratté S, Asante EA, Linehan J, Gowland I, Jefferys JG, Collinge J. Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 2002;21:202–210. [PubMed]
21. Baumann F, Tolnay M, Brabeck C, Pahnke J, Kloz U, Niemann HH, et al. Lethal recessive myelin toxicity of prion protein lacking its central domain. EMBO J. 2007;26:538–547. [PubMed]
22. Li A, Christensen HM, Stewart LR, Roth KA, Chiesa R, Harris DA. Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105–125. EMBO J. 2007;26:548–558. [PubMed]
23. Radovanovic I, Braun N, Giger OT, Mertz K, Miele G, Prinz M, et al. Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC. J Neurosci. 2005;25:4879–4888. [PubMed]
24. Moore RC, Lee IY, Silverman GL, Harrison PM, Strome R, Heinrich C, et al. Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J Mol Biol. 1999;292:797–817. [PubMed]
25. Vassallo N, Herms J. Cellular prion protein function in copper homeostasis and redox signalling at the synapse. J Neurochem. 2003;86:538–544. [PubMed]
26. McLennan NF, Brennan PM, McNeill A, Davies I, Fotheringham A, Rennison KA, et al. Prion protein accumulation and neuroprotection in hypoxic brain damage. Am J Pathol. 2004;165:227–235. [PubMed]
27. Shyu WC, Lin SZ, Chiang MF, Ding DC, Li KW, Chen SF, et al. Overexpression of PrPC by adenovirus-mediated gene targeting reduces ischemic injury in a stroke rat model. J Neurosci. 2005;25:8967–8977. [PubMed]
28. Spudich A, Frigg R, Kilic E, Kilic U, Oesch B, Raeber A, et al. Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1. Neurobiol Dis. 2005;20:442–449. [PubMed]
29. Weise J, Crome O, Sandau R, Schulz-Schaeffer W, Bahr M, Zerr I. Upregulation of cellular prion protein (PrPc) after focal cerebral ischemia and influence of lesion severity. Neurosci Lett. 2004;372:146–150. [PubMed]
30. Walz R, Amaral OE, Rockenbach IC, Roesler R, Izquierdo I, Cavalheiro EA, et al. Increased sensitivity to seizures in mice lacking cellular prion protein. Epilepsia. 1999;40:1679–1682. [PubMed]
31. Rangel A, Burgaya F, Gavin R, Soriano E, Aguzzi A, Del Rio JA. Enhanced susceptibility of Prnp-deficient mice to kainate-induced seizures, neuronal apoptosis and death: Role of AMPA/kainate receptors. J Neurosci Res. 2007;85:2741–2755. [PubMed]
32. Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009;457:1128–1132. [PMC free article] [PubMed]
33. Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci. 2004;61:657–668. [PubMed]
34. Mody I, MacDonald JF. NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol Sci. 1995;16:356–359. [PubMed]
35. Olney JW, Collins RC, Sloviter RS. Excitotoxic mechanisms of epileptic brain damage. Adv Neurol. 1986;44:857–877. [PubMed]
36. Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, et al. NMDA receptors mediate Ca accumulation in central nervous system myelin during chemical ischemia. Nature. 2006;439:988–992. [PubMed]
37. Khosravani H, Zhang Y, Tsutsui S, Hameed S, Altier C, Hamid J, et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J Cell Biol. 2008;181:551–565. [PMC free article] [PubMed]
38. Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004;255:16. [PubMed]
39. Riemer C, Burwinkel M, Schwarz A, Gültner S, Mok SW, Heise I, et al. Evaluation of drugs for treatment of prion infections of the central nervous system. J Gen Virol. 2008;89:594–597. [PubMed]

Articles from Prion are provided here courtesy of Taylor & Francis