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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2015

Open Access 01-12-2015 | Research

Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases

Authors: Joan Torrent, Alba Vilchez-Acosta, Diego Muñoz-Torrero, Marie Trovaslet, Florian Nachon, Arnaud Chatonnet, Katarina Grznarova, Isabelle Acquatella-Tran Van Ba, Ronan Le Goffic, Laetitia Herzog, Vincent Béringue, Human Rezaei

Published in: Acta Neuropathologica Communications | Issue 1/2015

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Abstract

Introduction

The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases

Results

Here, we show that PrP can interact in vitro with acetylcholinesterase (AChE), a key protein of the cholinergic system in neural and non-neural tissues. This heterologous association induced aggregation of monomeric PrP and modified the structural properties of PrP amyloid fibrils. Following its recruitment into PrP fibrils, AChE loses its enzymatic activity and enhances PrP-mediated cytotoxicity. Using several truncated PrP variants and specific tight-binding AChE inhibitors (AChEis), we then demonstrate that the PrP-AChE interaction requires two mutually exclusive sub-sites in PrP N-terminal domain and an aromatic-rich region at the entrance of AChE active center gorge. We show that AChEis that target this site impair PrP-AChE complex formation and also limit the accumulation of pathological prion protein (PrPSc) in prion-infected cell cultures. Furthermore, reduction of AChE levels in prion-infected heterozygous AChE knock-out mice leads to slightly but significantly prolonged incubation time. Finally, we found that AChE levels were altered in prion-infected cells and tissues, suggesting that AChE might be directly associated with abnormal PrP.

Conclusion

Our results indicate that AChE deserves consideration as a new actor in expanding pathologically relevant PrP morphotypes and as a therapeutic target.
Appendix
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Literature
1.
Castilla J, Saa P, Hetz C, Soto C (2005) In vitro generation of infectious scrapie prions. Cell 121(2):195–206, doi:10.1016/j.cell.2005.02.011PubMedCrossRef
2.
Deleault NR, Harris BT, Rees JR, Supattapone S (2007) Formation of native prions from minimal components in vitro. Proc Natl Acad Sci U S A 104(23):9741–6, doi:10.1073/pnas.0702662104PubMedCentralPubMedCrossRef
3.
Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216(4542):136–44PubMedCrossRef
4.
Aguzzi A, Baumann F, Bremer J (2008) The prion’s elusive reason for being. Annu Rev Neurosci 31:439–77, doi:10.1146/annurev.neuro.31.060407.125620PubMedCrossRef
5.
Lee KS, Linden R, Prado MA, Brentani RR, Martins VR (2003) Towards cellular receptors for prions. Rev Med Virol 13(6):399–408, doi:10.1002/rmv.408PubMedCrossRef
6.
Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR (2008) Physiology of the prion protein. Physiol Rev 88(2):673–728, doi:10.1152/physrev.00007.2007PubMedCrossRef
7.
Schneider B, Pietri M, Pradines E, Loubet D, Launay JM, Kellermann O et al (2011) Understanding the neurospecificity of Prion protein signaling. Front Biosci 16:169–86CrossRef
8.
Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J et al (2012) Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. Proc Natl Acad Sci U S A 109(28):E1938–46, doi:10.1073/pnas.1206999109PubMedCentralPubMedCrossRef
9.
10.
Aguzzi A, Heikenwalder M, Polymenidou M (2007) Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8(7):552–61, doi:10.1038/nrm2204PubMedCrossRef
11.
Eichner T, Radford SE (2011) A diversity of assembly mechanisms of a generic amyloid fold. Mol Cell 43(1):8–18, doi:10.1016/j.molcel.2011.05.012PubMedCrossRef
12.
Hicks D, John D, Makova NZ, Henderson Z, Nalivaeva NN, Turner AJ (2011) Membrane targeting, shedding and protein interactions of brain acetylcholinesterase. J Neurochem 116(5):742–6, doi:10.1111/j.1471-4159.2010.07032.xPubMedCrossRef
13.
Xie HQ, Liang D, Leung KW, Chen VP, Zhu KY, Chan WK et al (2010) Targeting acetylcholinesterase to membrane rafts: a function mediated by the proline-rich membrane anchor (PRiMA) in neurons. J Biol Chem 285(15):11537–46, doi:10.1074/jbc.M109.038711PubMedCentralPubMedCrossRef
14.
Layer PG (1995) Nonclassical roles of cholinesterases in the embryonic brain and possible links to Alzheimer disease. Alzheimer Dis Assoc Disord 9(Suppl 2):29–36PubMedCrossRef
15.
Silman I, Sussman JL (2005) Acetylcholinesterase: ‘classical’ and ‘non-classical’ functions and pharmacology. Curr Opin Pharmacol 5(3):293–302, doi:10.1016/j.coph.2005.01.014PubMedCrossRef
16.
Greenfield SA, Zimmermann M, Bond CE (2008) Non-hydrolytic functions of acetylcholinesterase. The significance of C-terminal peptides. FEBS J 275(4):604–11, doi:10.1111/j.1742-4658.2007.06235.xPubMedCrossRef
17.
Soreq H, Seidman S (2001) Acetylcholinesterase–new roles for an old actor. Nat Rev Neurosci 2(4):294–302, doi:10.1038/35067589PubMedCrossRef
18.
Dinamarca MC, Sagal JP, Quintanilla RA, Godoy JA, Arrazola MS, Inestrosa NC (2010) Amyloid-beta-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer’s disease. Mol Neurodegener 5:4, doi:10.1186/1750-1326-5-4PubMedCentralPubMedCrossRef
19.
Inestrosa NC, Dinamarca MC, Alvarez A (2008) Amyloid-cholinesterase interactions. Implications for Alzheimer’s disease. FEBS J 275(4):625–32, doi:10.1111/j.1742-4658.2007.06238.xPubMedCrossRef
20.
Reyes AE, Chacon MA, Dinamarca MC, Cerpa W, Morgan C, Inestrosa NC (2004) Acetylcholinesterase-Abeta complexes are more toxic than Abeta fibrils in rat hippocampus: effect on rat beta-amyloid aggregation, laminin expression, reactive astrocytosis, and neuronal cell loss. Am J Pathol 164(6):2163–74PubMedCentralPubMedCrossRef
21.
Rees T, Hammond PI, Soreq H, Younkin S, Brimijoin S (2003) Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol Aging 24(6):777–87PubMedCrossRef
22.
Rees TM, Berson A, Sklan EH, Younkin L, Younkin S, Brimijoin S et al (2005) Memory deficits correlating with acetylcholinesterase splice shift and amyloid burden in doubly transgenic mice. Curr Alzheimer Res 2(3):291–300PubMedCrossRef
23.
De Ferrari GV, Canales MA, Shin I, Weiner LM, Silman I, Inestrosa NC (2001) A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry 40(35):10447–57PubMedCrossRef
24.
Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L et al (1991) Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science 253(5022):872–9PubMedCrossRef
25.
Taylor P, Lappi S (1975) Interaction of fluorescence probes with acetylcholinesterase. The site and specificity of propidium binding. Biochemistry 14(9):1989–97PubMedCrossRef
26.
Castro A, Martinez A (2006) Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Curr Pharm Des 12(33):4377–87PubMedCrossRef
27.
Holzgrabe U, Kapkova P, Alptuzun V, Scheiber J, Kugelmann E (2007) Targeting acetylcholinesterase to treat neurodegeneration. Expert Opin Ther Targets 11(2):161–79, doi:10.1517/14728222.11.2.161PubMedCrossRef
28.
Munoz-Torrero D (2008) Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer’s disease. Curr Med Chem 15(24):2433–55PubMedCrossRef
29.
Rampa A, Belluti F, Gobbi S, Bisi A (2011) Hybrid-based multi-target ligands for the treatment of Alzheimer’s disease. Curr Top Med Chem 11(22):2716–30PubMedCrossRef
30.
Pera M, Martinez-Otero A, Colombo L, Salmona M, Ruiz-Molina D, Badia A et al (2009) Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process. Mol Cell Neurosci 40(2):217–24, doi:0.1016/j.mcn.2008.10.008PubMedCrossRef
31.
Pera M, Roman S, Ratia M, Camps P, Munoz-Torrero D, Colombo L et al (2006) Acetylcholinesterase triggers the aggregation of PrP 106–126. Biochem Biophys Res Commun 346(1):89–94, doi:10.1016/j.bbrc.2006.04.187PubMedCrossRef
32.
Silveyra MX, Cuadrado-Corrales N, Marcos A, Barquero MS, Rabano A, Calero M et al (2006) Altered glycosylation of acetylcholinesterase in Creutzfeldt-Jakob disease. J Neurochem 96(1):97–104, doi:10.1111/j.1471-4159.2005.03514.xPubMedCrossRef
33.
Silveyra MX, Garcia-Ayllon MS, Calero M, Saez-Valero J (2006) Altered glycosylation of acetylcholinesterase in the Creutzfeldt-Jakob cerebrospinal fluid. J Mol Neurosci: MN 30(1–2):65–6, doi:10.1385/JMN:30:1:65PubMedCrossRef
34.
Rezaei H, Marc D, Choiset Y, Takahashi M, Hui Bon Hoa G, Haertle T et al (2000) High yield purification and physico-chemical properties of full-length recombinant allelic variants of sheep prion protein linked to scrapie susceptibility. Eur J Biochem/FEBS 267(10):2833–9CrossRef
35.
Carletti E, Li H, Li B, Ekstrom F, Nicolet Y, Loiodice M et al (2008) Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation. J Am Chem Soc 130(47):16011–20, doi:10.1021/ja804941zPubMedCrossRef
36.
Camps P, Contreras J, Font-Bardia M, Morral J, Munoz-Torrero D, Solans X (1998) Enantioselective synthesis of tacrine − huperzine A hybrids. Preparative chiral MPLC separation of their racemic mixtures and absolute configuration assignments by X-ray diffraction analysis. Tetrahedron Asymmetry 9(9):835–49CrossRef
37.
Camps P, Formosa X, Munoz-Torrero D, Petrignet J, Badia A, Clos MV (2005) Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors. J Med Chem 48(6):1701–4, doi:10.1021/jm0496741PubMedCrossRef
38.
Archer F, Bachelin C, Andreoletti O, Besnard N, Perrot G, Langevin C et al (2004) Cultured peripheral neuroglial cells are highly permissive to sheep prion infection. J Virol 78(1):482–90PubMedCentralPubMedCrossRef
39.
Vilette D, Andreoletti O, Archer F, Madelaine MF, Vilotte JL, Lehmann S et al (2001) Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc Natl Acad Sci U S A 98(7):4055–9, doi:10.1073/pnas.061337998PubMedCentralPubMedCrossRef
40.
Feraudet C, Morel N, Simon S, Volland H, Frobert Y, Creminon C et al (2005) Screening of 145 anti-PrP monoclonal antibodies for their capacity to inhibit PrPSc replication in infected cells. J Biol Chem 280(12):11247–58, doi:10.1074/jbc.M407006200PubMedCrossRef
41.
Jennings LL, Malecki M, Komives EA, Taylor P (2003) Direct analysis of the kinetic profiles of organophosphate-acetylcholinesterase adducts by MALDI-TOF mass spectrometry. Biochemistry 42(37):11083–91, doi:10.1021/bi034756xPubMedCrossRef
42.
Breydo L, Makarava N, Baskakov IV (2008) Methods for conversion of prion protein into amyloid fibrils. Methods Mol Biol 459:105–15, doi:10.1007/978-1-59745-234-2_8PubMedCrossRef
43.
Bocharova OV, Makarava N, Breydo L, Anderson M, Salnikov VV, Baskakov IV (2006) Annealing prion protein amyloid fibrils at high temperature results in extension of a proteinase K-resistant core. J Biol Chem 281(4):2373–9, doi:10.1074/jbc.M510840200PubMedCrossRef
44.
El Moustaine D, Perrier V, Acquatella-Tran Van Ba I, Meersman F, Ostapchenko VG, Baskakov IV et al (2011) Amyloid features and neuronal toxicity of mature prion fibrils are highly sensitive to high pressure. J Biol Chem 286(15):13448–59, doi:10.1074/jbc.M110.192872PubMedCentralPubMedCrossRef
45.
Tixador P, Herzog L, Reine F, Jaumain E, Chapuis J, Le Dur A et al (2010) The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog 6(4):e1000859, doi:10.1371/journal.ppat.1000859PubMedCentralPubMedCrossRef
46.
Beringue V, Andreoletti O, Le Dur A, Essalmani R, Vilotte JL, Lacroux C et al (2007) A bovine prion acquires an epidemic bovine spongiform encephalopathy strain-like phenotype on interspecies transmission. J Neurosci: Offic J Soc Neurosci 27(26):6965–71, doi:10.1523/JNEUROSCI. 0693-07.2007CrossRef
47.
Oumata N, Nguyen PH, Beringue V, Soubigou F, Pang Y, Desban N et al (2013) The toll-like receptor agonist imiquimod is active against prions. PLoS One 8(8):e72112, doi:10.1371/journal.pone.0072112PubMedCentralPubMedCrossRef
48.
Tribouillard-Tanvier D, Beringue V, Desban N, Gug F, Bach S, Voisset C et al (2008) Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions. PLoS One 3(4):e1981, doi:10.1371/journal.pone.0001981PubMedCentralPubMedCrossRef
49.
Camps P, El Achab R, Morral J, Munoz-Torrero D, Badia A, Banos JE et al (2000) New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer’s disease. J Med Chem 43(24):4657–66PubMedCrossRef
50.
Rezaei H, Choiset Y, Eghiaian F, Treguer E, Mentre P, Debey P et al (2002) Amyloidogenic unfolding intermediates differentiate sheep prion protein variants. J Mol Biol 322(4):799–814PubMedCrossRef
51.
Baskakov IV, Legname G, Baldwin MA, Prusiner SB, Cohen FE (2002) Pathway complexity of prion protein assembly into amyloid. J Biol Chem 277(24):21140–8, doi:10.1074/jbc.M111402200PubMedCrossRef
52.
Espallergues J, Galvan L, Sabatier F, Rana-Poussine V, Maurice T, Chatonnet A (2010) Behavioral phenotyping of heterozygous acetylcholinesterase knockout (AChE+/−) mice showed no memory enhancement but hyposensitivity to amnesic drugs. Behav Brain Res 206(2):263–73, doi:10.1016/j.bbr.2009.09.024PubMedCrossRef
53.
Collinge J (2001) Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24:519–50, doi:10.1146/annurev.neuro.24.1.519PubMedCrossRef
54.
55.
Makarava N, Kovacs GG, Bocharova O, Savtchenko R, Alexeeva I, Budka H et al (2010) Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol 119(2):177–87, doi:10.1007/s00401-009-0633-xPubMedCentralPubMedCrossRef
56.
Zhang Z, Zhang Y, Wang F, Wang X, Xu Y, Yang H, et al (2013) De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. doi:10.1096/fj.13-233965
57.
Duysen EG, Li B, Xie W, Schopfer LM, Anderson RS, Broomfield CA et al (2001) Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: supersensitivity of acetylcholinesterase knockout mouse to VX lethality. J Pharmacol Exp Ther 299(2):528–35PubMed
58.
Moore RA, Timmes A, Wilmarth PA, Priola SA (2010) Comparative profiling of highly enriched 22 L and Chandler mouse scrapie prion protein preparations. Proteomics 10(15):2858–69, doi:10.1002/pmic.201000104PubMedCentralPubMedCrossRef
59.
Galdeano C, Viayna E, Sola I, Formosa X, Camps P, Badia A et al (2012) Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion diseases. J Med Chem 55(2):661–9, doi:10.1021/jm200840cPubMedCrossRef
60.
Cobb NJ, Sonnichsen FD, McHaourab H, Surewicz WK (2007) Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure. Proc Natl Acad Sci U S A 104(48):18946–51, doi:10.1073/pnas.0706522104PubMedCentralPubMedCrossRef
61.
Lu X, Wintrode PL, Surewicz WK (2007) Beta-sheet core of human prion protein amyloid fibrils as determined by hydrogen/deuterium exchange. Proc Natl Acad Sci U S A 104(5):1510–5, doi:10.1073/pnas.0608447104PubMedCentralPubMedCrossRef
62.
Makarava N, Baskakov IV (2008) The same primary structure of the prion protein yields two distinct self-propagating states. J Biol Chem 283(23):15988–96, doi:10.1074/jbc.M800562200PubMedCentralPubMedCrossRef
63.
Ostapchenko VG, Sawaya MR, Makarava N, Savtchenko R, Nilsson KP, Eisenberg D et al (2010) Two amyloid States of the prion protein display significantly different folding patterns. J Mol Biol 400(4):908–21, doi:10.1016/j.jmb.2010.05.051PubMedCentralPubMedCrossRef
64.
Tycko R, Savtchenko R, Ostapchenko VG, Makarava N, Baskakov IV (2010) The alpha-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel beta-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance. Biochemistry 49(44):9488–97, doi:10.1021/bi1013134PubMedCentralPubMedCrossRef
65.
Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL (2010) Acetylcholinesterase: from 3D structure to function. Chem Biol Interact 187(1–3):10–22, doi:10.1016/j.cbi.2010.01.042PubMedCentralPubMedCrossRef
66.
Beringue V, Herzog L, Jaumain E, Reine F, Sibille P, Le Dur A et al (2012) Facilitated cross-species transmission of prions in extraneural tissue. Science 335(6067):472–5, doi:10.1126/science.1215659PubMedCrossRef
67.
68.
Bellinger DL, Lorton D, Hamill RW, Felten SY, Felten DL (1993) Acetylcholinesterase staining and choline acetyltransferase activity in the young adult rat spleen: lack of evidence for cholinergic innervation. Brain Behav Immun 7(3):191–204, doi:10.1006/brbi.1993.1021PubMedCrossRef
69.
Lampert IA, Van Noorden S (1996) Acetyl cholinesterase is expressed in the follicular dendritic cells of germinal centres: differences between normal and neoplastic follicles. J Pathol 180(2):169–74, doi:10.1002/(SICI)1096-9896(199610)180:2<169::AID-PATH621>3.0.CO;2-DPubMedCrossRef
70.
Dron M, Moudjou M, Chapuis J, Salamat MK, Bernard J, Cronier S et al (2010) Endogenous proteolytic cleavage of disease-associated prion protein to produce C2 fragments is strongly cell- and tissue-dependent. J Biol Chem 285(14):10252–64, doi:10.1074/jbc.M109.083857PubMedCentralPubMedCrossRef
71.
Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233):1128–32, doi:10.1038/nature07761PubMedCentralPubMedCrossRef
Metadata
Title
Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
Authors
Joan Torrent
Alba Vilchez-Acosta
Diego Muñoz-Torrero
Marie Trovaslet
Florian Nachon
Arnaud Chatonnet
Katarina Grznarova
Isabelle Acquatella-Tran Van Ba
Ronan Le Goffic
Laetitia Herzog
Vincent Béringue
Human Rezaei
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-015-0188-0

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