TY  - JOUR
AU  - Llorens Torres, Francesc Josep
AU  - Thüne, Katrin
AU  - Sikorska, Beata
AU  - Schmitz, Matthias
AU  - Tahir, Waqas
AU  - Fernández-Borges, Natalia
AU  - Cramm, Maria
AU  - Gotzmann, Nadine
AU  - Carmona, Margarita
AU  - Streichenberger, Nathalie
AU  - Michel, Uwe
AU  - Zafar, Saima
AU  - Schütz, Anna-Lena
AU  - Rajput, Ashish
AU  - Andréoletti, Olivier
AU  - Bonn, Stefan
AU  - Fischer, Andre
AU  - Liberski, Pawel P
AU  - Torres, Juan Maria
AU  - Ferrer, Isidre
AU  - Zerr, Inga
TI  - Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.
JO  - Acta Neuropathologica Communications
VL  - 5
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2020-05561
SP  - 35
PY  - 2017
AB  - 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.
KW  - Animals
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Calcium: metabolism
KW  - Calpain: metabolism
KW  - Cathepsins: metabolism
KW  - Cations, Divalent: metabolism
KW  - Cells, Cultured
KW  - Creutzfeldt-Jakob Syndrome: metabolism
KW  - Creutzfeldt-Jakob Syndrome: pathology
KW  - Disease Models, Animal
KW  - Homeostasis: physiology
KW  - Humans
KW  - Lysosomes: metabolism
KW  - Lysosomes: pathology
KW  - Mesocricetus
KW  - Mice, Transgenic
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - PrPSc Proteins: metabolism
KW  - Rats, Wistar
KW  - Recombinant Proteins: metabolism
KW  - Sheep
KW  - Cations, Divalent (NLM Chemicals)
KW  - PrPSc Proteins (NLM Chemicals)
KW  - Recombinant Proteins (NLM Chemicals)
KW  - Cathepsins (NLM Chemicals)
KW  - Calpain (NLM Chemicals)
KW  - Calcium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28449707
C2  - pmc:PMC5408381
DO  - DOI:10.1186/s40478-017-0431-y
UR  - https://pub.dzne.de/record/139239
ER  -