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000139239 041__ $$aEnglish
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000139239 1001_ $$0P:(DE-2719)2811280$$aLlorens Torres, Francesc Josep$$b0$$eFirst author$$udzne
000139239 245__ $$aAltered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.
000139239 260__ $$aLondon$$bBiomed Central$$c2017
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000139239 520__ $$aSporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca2+) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca2+ responsive genes in sCJD brain tissue, accompanied by two Ca2+-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca2+ homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.
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000139239 650_7 $$2NLM Chemicals$$aCations, Divalent
000139239 650_7 $$2NLM Chemicals$$aPrPSc Proteins
000139239 650_7 $$2NLM Chemicals$$aRecombinant Proteins
000139239 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aCathepsins
000139239 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aCalpain
000139239 650_7 $$0SY7Q814VUP$$2NLM Chemicals$$aCalcium
000139239 650_2 $$2MeSH$$aAnimals
000139239 650_2 $$2MeSH$$aBrain: metabolism
000139239 650_2 $$2MeSH$$aBrain: pathology
000139239 650_2 $$2MeSH$$aCalcium: metabolism
000139239 650_2 $$2MeSH$$aCalpain: metabolism
000139239 650_2 $$2MeSH$$aCathepsins: metabolism
000139239 650_2 $$2MeSH$$aCations, Divalent: metabolism
000139239 650_2 $$2MeSH$$aCells, Cultured
000139239 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: metabolism
000139239 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: pathology
000139239 650_2 $$2MeSH$$aDisease Models, Animal
000139239 650_2 $$2MeSH$$aHomeostasis: physiology
000139239 650_2 $$2MeSH$$aHumans
000139239 650_2 $$2MeSH$$aLysosomes: metabolism
000139239 650_2 $$2MeSH$$aLysosomes: pathology
000139239 650_2 $$2MeSH$$aMesocricetus
000139239 650_2 $$2MeSH$$aMice, Transgenic
000139239 650_2 $$2MeSH$$aNeurons: metabolism
000139239 650_2 $$2MeSH$$aNeurons: pathology
000139239 650_2 $$2MeSH$$aPrPSc Proteins: metabolism
000139239 650_2 $$2MeSH$$aRats, Wistar
000139239 650_2 $$2MeSH$$aRecombinant Proteins: metabolism
000139239 650_2 $$2MeSH$$aSheep
000139239 7001_ $$0P:(DE-2719)2811840$$aThüne, Katrin$$b1$$udzne
000139239 7001_ $$0P:(DE-HGF)0$$aSikorska, Beata$$b2
000139239 7001_ $$0P:(DE-2719)9000287$$aSchmitz, Matthias$$b3$$udzne
000139239 7001_ $$0P:(DE-2719)9000310$$aTahir, Waqas$$b4$$udzne
000139239 7001_ $$0P:(DE-HGF)0$$aFernández-Borges, Natalia$$b5
000139239 7001_ $$0P:(DE-2719)2810657$$aCramm, Maria$$b6$$udzne
000139239 7001_ $$0P:(DE-2719)2811365$$aGotzmann, Nadine$$b7$$udzne
000139239 7001_ $$0P:(DE-HGF)0$$aCarmona, Margarita$$b8
000139239 7001_ $$0P:(DE-HGF)0$$aStreichenberger, Nathalie$$b9
000139239 7001_ $$0P:(DE-2719)9000211$$aMichel, Uwe$$b10$$udzne
000139239 7001_ $$0P:(DE-2719)9000358$$aZafar, Saima$$b11$$udzne
000139239 7001_ $$0P:(DE-2719)2810585$$aSchütz, Anna-Lena$$b12$$udzne
000139239 7001_ $$0P:(DE-2719)2811012$$aRajput, Ashish$$b13$$udzne
000139239 7001_ $$0P:(DE-HGF)0$$aAndréoletti, Olivier$$b14
000139239 7001_ $$0P:(DE-2719)2810547$$aBonn, Stefan$$b15$$udzne
000139239 7001_ $$0P:(DE-2719)2000047$$aFischer, Andre$$b16$$udzne
000139239 7001_ $$0P:(DE-HGF)0$$aLiberski, Pawel P$$b17
000139239 7001_ $$0P:(DE-HGF)0$$aTorres, Juan Maria$$b18
000139239 7001_ $$0P:(DE-HGF)0$$aFerrer, Isidre$$b19
000139239 7001_ $$0P:(DE-2719)2000058$$aZerr, Inga$$b20$$eLast author$$udzne
000139239 77318 $$2Crossref$$3journal-article$$a10.1186/s40478-017-0431-y$$b : Springer Science and Business Media LLC, 2017-04-27$$n1$$p35$$tActa Neuropathologica Communications$$v5$$x2051-5960$$y2017
000139239 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-017-0431-y$$gVol. 5, no. 1, p. 35$$n1$$p35$$q5:1<35$$tActa Neuropathologica Communications$$v5$$x2051-5960$$y2017
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000139239 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408381
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000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/S1474-4422(12)70063-7$$o10.1016/S1474-4422(12)70063-7
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1054/ceca.2000.0190$$o10.1054/ceca.2000.0190
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.90.7.2628$$o10.1073/pnas.90.7.2628
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.nbd.2003.09.006$$o10.1016/j.nbd.2003.09.006
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/srep28711$$o10.1038/srep28711
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.tibs.2015.01.002$$o10.1016/j.tibs.2015.01.002
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/0006-8993(91)90722-8$$o10.1016/0006-8993(91)90722-8
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.biocel.2004.04.014$$o10.1016/j.biocel.2004.04.014
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.ppat.0030125$$o10.1371/journal.ppat.0030125
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1046/j.1471-4159.2003.01541.x$$o10.1046/j.1471-4159.2003.01541.x
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s11064-009-9960-5$$o10.1007/s11064-009-9960-5
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nrn1174$$o10.1038/nrn1174
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1176/appi.ajp.2013.12111460$$o10.1176/appi.ajp.2013.12111460
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.pone.0015658$$o10.1371/journal.pone.0015658
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.4161/cib.4.3.15019$$o10.4161/cib.4.3.15019
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.virusres.2014.12.018$$o10.1016/j.virusres.2014.12.018
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/S0304-3940(98)00348-6$$o10.1016/S0304-3940(98)00348-6
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1097/01.jnen.0000218445.30535.6f$$o10.1097/01.jnen.0000218445.30535.6f
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00401-004-0879-2$$o10.1007/s00401-004-0879-2
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1046/j.1365-2613.2000.00169.x$$o10.1046/j.1365-2613.2000.00169.x
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.bbamcr.2013.05.019$$o10.1016/j.bbamcr.2013.05.019
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s12035-008-8036-x$$o10.1007/s12035-008-8036-x
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/978-94-007-2888-2_54$$o10.1007/978-94-007-2888-2_54
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1128/jvi.78.20.11051-11060.2004$$o10.1128/jvi.78.20.11051-11060.2004
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.M400793200$$o10.1074/jbc.M400793200
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.neuroscience.2012.08.068$$o10.1016/j.neuroscience.2012.08.068
000139239 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.pneurobio.2013.02.004$$o10.1016/j.pneurobio.2013.02.004