Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/124403
Title: Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
Author: 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
Keywords: Malaltia de Creutzfeldt-Jakob
Prions
Calci
Creutzfeldt-Jakob disease
Calcium
Issue Date: 27-Apr-2017
Publisher: BioMed Central
Abstract: 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.
Note: Reproducció del document publicat a: https://doi.org/10.1186/s40478-017-0431-y
It is part of: Acta Neuropathologica Communications, 2017, vol. 5, num. 35
URI: http://hdl.handle.net/2445/124403
Related resource: https://doi.org/10.1186/s40478-017-0431-y
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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