Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underly...

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Autores: Llorens Torres, Franc, Thüne, Katrin, Sikorska, Beata, Schmitz, Matthias, Tahir, Waqas, Fernández Borges, Natalia, Cramm, Maria, Gotzmann, Nadine, Carmona Murillo, Margarita, Streichenberger, Nathalie, Michel, Uwe, Zafar, Saima, Schuetz, Anna-Lena, Rajput, Ashish, Andreoletti, Olivier, Bonn, Stefan, Fischer, Andre, Liberski, Pawel P., Torres, Juan Maria, Ferrer, Isidro (Ferrer Abizanda), Zerr, Inga
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/124403
Acceso en línea:https://hdl.handle.net/2445/124403
Access Level:acceso abierto
Palabra clave:Malaltia de Creutzfeldt-Jakob
Prions
Calci
Creutzfeldt-Jakob disease
Calcium
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spelling Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob diseaseLlorens Torres, FrancThüne, KatrinSikorska, BeataSchmitz, MatthiasTahir, WaqasFernández Borges, NataliaCramm, MariaGotzmann, NadineCarmona Murillo, MargaritaStreichenberger, NathalieMichel, UweZafar, SaimaSchuetz, Anna-LenaRajput, AshishAndreoletti, OlivierBonn, StefanFischer, AndreLiberski, Pawel P.Torres, Juan MariaFerrer, Isidro (Ferrer Abizanda)Zerr, IngaMalaltia de Creutzfeldt-JakobPrionsCalciCreutzfeldt-Jakob diseaseCalciumSporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca2+) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca2+ responsive genes in sCJD brain tissue, accompanied by two Ca2+-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca2+ homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.BioMed Central2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/124403Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s40478-017-0431-yActa Neuropathologica Communications, 2017, vol. 5, num. 35https://doi.org/10.1186/s40478-017-0431-ycc by (c) Llorens et al., 2017http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1244032026-05-27T06:46:51Z
dc.title.none.fl_str_mv Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
title Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
spellingShingle Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
Llorens Torres, Franc
Malaltia de Creutzfeldt-Jakob
Prions
Calci
Creutzfeldt-Jakob disease
Calcium
title_short Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
title_full Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
title_fullStr Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
title_full_unstemmed Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
title_sort Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
dc.creator.none.fl_str_mv Llorens Torres, Franc
Thüne, Katrin
Sikorska, Beata
Schmitz, Matthias
Tahir, Waqas
Fernández Borges, Natalia
Cramm, Maria
Gotzmann, Nadine
Carmona Murillo, Margarita
Streichenberger, Nathalie
Michel, Uwe
Zafar, Saima
Schuetz, Anna-Lena
Rajput, Ashish
Andreoletti, Olivier
Bonn, Stefan
Fischer, Andre
Liberski, Pawel P.
Torres, Juan Maria
Ferrer, Isidro (Ferrer Abizanda)
Zerr, Inga
author Llorens Torres, Franc
author_facet Llorens Torres, Franc
Thüne, Katrin
Sikorska, Beata
Schmitz, Matthias
Tahir, Waqas
Fernández Borges, Natalia
Cramm, Maria
Gotzmann, Nadine
Carmona Murillo, Margarita
Streichenberger, Nathalie
Michel, Uwe
Zafar, Saima
Schuetz, Anna-Lena
Rajput, Ashish
Andreoletti, Olivier
Bonn, Stefan
Fischer, Andre
Liberski, Pawel P.
Torres, Juan Maria
Ferrer, Isidro (Ferrer Abizanda)
Zerr, Inga
author_role author
author2 Thüne, Katrin
Sikorska, Beata
Schmitz, Matthias
Tahir, Waqas
Fernández Borges, Natalia
Cramm, Maria
Gotzmann, Nadine
Carmona Murillo, Margarita
Streichenberger, Nathalie
Michel, Uwe
Zafar, Saima
Schuetz, Anna-Lena
Rajput, Ashish
Andreoletti, Olivier
Bonn, Stefan
Fischer, Andre
Liberski, Pawel P.
Torres, Juan Maria
Ferrer, Isidro (Ferrer Abizanda)
Zerr, Inga
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia de Creutzfeldt-Jakob
Prions
Calci
Creutzfeldt-Jakob disease
Calcium
topic Malaltia de Creutzfeldt-Jakob
Prions
Calci
Creutzfeldt-Jakob disease
Calcium
description Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca2+) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca2+ responsive genes in sCJD brain tissue, accompanied by two Ca2+-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca2+ homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.
publishDate 2017
dc.date.none.fl_str_mv 2017
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/2445/124403
url https://hdl.handle.net/2445/124403
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s40478-017-0431-y
Acta Neuropathologica Communications, 2017, vol. 5, num. 35
https://doi.org/10.1186/s40478-017-0431-y
dc.rights.none.fl_str_mv cc by (c) Llorens et al., 2017
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Llorens et al., 2017
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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 (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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