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

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

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Authors: Torrent, Joan, Vílchez Acosta, Alba del Valle, Muñoz-Torrero López-Ibarra, Diego, Trovaslet, M., Nachon, Florian, Chatonnet, A., Grznarova, K., Acquatella-Tran Van Ba, I., Goffic, R. Le, Herzog, Laetitia, Béringue, V., Rezaei, H.
Format: article
Status:Published version
Publication Date:2015
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/66823
Online Access:https://hdl.handle.net/2445/66823
Access Level:Open access
Keyword:Amiloïdosi
Malalties neurodegeneratives
Proteïnes
Amyloidosis
Neurodegenerative Diseases
Proteins
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oai_identifier_str oai:recercat.cat:2445/66823
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repository_id_str
spelling Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseasesTorrent, JoanVílchez Acosta, Alba del ValleMuñoz-Torrero López-Ibarra, DiegoTrovaslet, M.Nachon, FlorianChatonnet, A.Grznarova, K.Acquatella-Tran Van Ba, I.Goffic, R. LeHerzog, LaetitiaBéringue, V.Rezaei, H.AmiloïdosiMalalties neurodegenerativesProteïnesAmyloidosisNeurodegenerative DiseasesProteinsThe prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases. 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. Our results indicate that AChE deserves consideration as a new actor in expanding pathologically relevant PrP morphotypes and as a therapeutic target.BioMed Central2015201520152015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion18 p.application/pdfhttps://hdl.handle.net/2445/66823Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: http://dx.doi.org/10.1186/s40478-015-0188-0Acta Neuropathologica Communications, 2015, vol. 3, num. 18http://dx.doi.org/10.1186/s40478-015-0188-0cc-by (c) Torrent et al., 2015http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/668232026-05-29T05:05:01Z
dc.title.none.fl_str_mv Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
title Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
spellingShingle Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
Torrent, Joan
Amiloïdosi
Malalties neurodegeneratives
Proteïnes
Amyloidosis
Neurodegenerative Diseases
Proteins
title_short Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
title_full Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
title_fullStr Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
title_full_unstemmed Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
title_sort Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases
dc.creator.none.fl_str_mv Torrent, Joan
Vílchez Acosta, Alba del Valle
Muñoz-Torrero López-Ibarra, Diego
Trovaslet, M.
Nachon, Florian
Chatonnet, A.
Grznarova, K.
Acquatella-Tran Van Ba, I.
Goffic, R. Le
Herzog, Laetitia
Béringue, V.
Rezaei, H.
author Torrent, Joan
author_facet Torrent, Joan
Vílchez Acosta, Alba del Valle
Muñoz-Torrero López-Ibarra, Diego
Trovaslet, M.
Nachon, Florian
Chatonnet, A.
Grznarova, K.
Acquatella-Tran Van Ba, I.
Goffic, R. Le
Herzog, Laetitia
Béringue, V.
Rezaei, H.
author_role author
author2 Vílchez Acosta, Alba del Valle
Muñoz-Torrero López-Ibarra, Diego
Trovaslet, M.
Nachon, Florian
Chatonnet, A.
Grznarova, K.
Acquatella-Tran Van Ba, I.
Goffic, R. Le
Herzog, Laetitia
Béringue, V.
Rezaei, H.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Amiloïdosi
Malalties neurodegeneratives
Proteïnes
Amyloidosis
Neurodegenerative Diseases
Proteins
topic Amiloïdosi
Malalties neurodegeneratives
Proteïnes
Amyloidosis
Neurodegenerative Diseases
Proteins
description The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases. 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. Our results indicate that AChE deserves consideration as a new actor in expanding pathologically relevant PrP morphotypes and as a therapeutic target.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/66823
url https://hdl.handle.net/2445/66823
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1186/s40478-015-0188-0
Acta Neuropathologica Communications, 2015, vol. 3, num. 18
http://dx.doi.org/10.1186/s40478-015-0188-0
dc.rights.none.fl_str_mv cc-by (c) Torrent et al., 2015
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Torrent et al., 2015
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 18 p.
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404742736674816
score 15,811543

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