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, Franc, Thüne, Katrin, Sikorska, B., Schmitz, Matthias, Tahir, W., Fernández-Borges, N., Cramm, M., Gotzmann, N., Carmona, Manuel, Streichenberger, N., Michel, U., Zafar, S., Schuetz, A. L., Rajput, A., Andréoletti, Olivier, Bonn, S., Fischer, A., Liberski, P. P., Torres, Juan María, Ferrer, Isidre, Zerr, I.
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/291630
Acceso en línea:http://hdl.handle.net/10261/291630
Access Level:acceso abierto
Palabra clave:Creutzfeldt-Jakob disease
Prion protein
Calpain
Cathepsin
Calcium
Ca2+
ddc:610
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repository_id_str
spelling Altered Ca2+ homeostasis induces Calpain- Cathepsin axis activation in sporadic Creutzfeldt-Jakob diseaseLlorens, FrancThüne, KatrinSikorska, B.Schmitz, MatthiasTahir, W.Fernández-Borges, N.Cramm, M.Gotzmann, N.Carmona, ManuelStreichenberger, N.Michel, U.Zafar, S.Schuetz, A. L.Rajput, A.Andréoletti, OlivierBonn, S.Fischer, A.Liberski, P. P.Torres, Juan MaríaFerrer, IsidreZerr, I.Creutzfeldt-Jakob diseasePrion proteinCalpainCathepsinCalciumCa2+ddc:610Sporadic 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.Peer reviewedBioMed CentralConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/291630reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésCentro de Investigación en Sanidad Animal (CISA)Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2916302026-05-22T06:33:51Z
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, Franc
Creutzfeldt-Jakob disease
Prion protein
Calpain
Cathepsin
Calcium
Ca2+
ddc:610
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, Franc
Thüne, Katrin
Sikorska, B.
Schmitz, Matthias
Tahir, W.
Fernández-Borges, N.
Cramm, M.
Gotzmann, N.
Carmona, Manuel
Streichenberger, N.
Michel, U.
Zafar, S.
Schuetz, A. L.
Rajput, A.
Andréoletti, Olivier
Bonn, S.
Fischer, A.
Liberski, P. P.
Torres, Juan María
Ferrer, Isidre
Zerr, I.
author Llorens, Franc
author_facet Llorens, Franc
Thüne, Katrin
Sikorska, B.
Schmitz, Matthias
Tahir, W.
Fernández-Borges, N.
Cramm, M.
Gotzmann, N.
Carmona, Manuel
Streichenberger, N.
Michel, U.
Zafar, S.
Schuetz, A. L.
Rajput, A.
Andréoletti, Olivier
Bonn, S.
Fischer, A.
Liberski, P. P.
Torres, Juan María
Ferrer, Isidre
Zerr, I.
author_role author
author2 Thüne, Katrin
Sikorska, B.
Schmitz, Matthias
Tahir, W.
Fernández-Borges, N.
Cramm, M.
Gotzmann, N.
Carmona, Manuel
Streichenberger, N.
Michel, U.
Zafar, S.
Schuetz, A. L.
Rajput, A.
Andréoletti, Olivier
Bonn, S.
Fischer, A.
Liberski, P. P.
Torres, Juan María
Ferrer, Isidre
Zerr, I.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Creutzfeldt-Jakob disease
Prion protein
Calpain
Cathepsin
Calcium
Ca2+
ddc:610
topic Creutzfeldt-Jakob disease
Prion protein
Calpain
Cathepsin
Calcium
Ca2+
ddc:610
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
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/291630
url http://hdl.handle.net/10261/291630
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Centro de Investigación en Sanidad Animal (CISA)
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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