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@ARTICLE{LlorensTorres:139239,
      author       = {Llorens Torres, Francesc Josep and Thüne, Katrin and
                      Sikorska, Beata and Schmitz, Matthias and Tahir, Waqas and
                      Fernández-Borges, Natalia and Cramm, Maria and Gotzmann,
                      Nadine and Carmona, Margarita and Streichenberger, Nathalie
                      and Michel, Uwe and Zafar, Saima and Schütz, Anna-Lena and
                      Rajput, Ashish and Andréoletti, Olivier and Bonn, Stefan
                      and Fischer, Andre and Liberski, Pawel P and Torres, Juan
                      Maria and Ferrer, Isidre and Zerr, Inga},
      title        = {{A}ltered {C}a2+ homeostasis induces {C}alpain-{C}athepsin
                      axis activation in sporadic {C}reutzfeldt-{J}akob disease.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {5},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2020-05561},
      pages        = {35},
      year         = {2017},
      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.},
      keywords     = {Animals / Brain: metabolism / Brain: pathology / Calcium:
                      metabolism / Calpain: metabolism / Cathepsins: metabolism /
                      Cations, Divalent: metabolism / Cells, Cultured /
                      Creutzfeldt-Jakob Syndrome: metabolism / Creutzfeldt-Jakob
                      Syndrome: pathology / Disease Models, Animal / Homeostasis:
                      physiology / Humans / Lysosomes: metabolism / Lysosomes:
                      pathology / Mesocricetus / Mice, Transgenic / Neurons:
                      metabolism / Neurons: pathology / PrPSc Proteins: metabolism
                      / Rats, Wistar / Recombinant Proteins: metabolism / Sheep /
                      Cations, Divalent (NLM Chemicals) / PrPSc Proteins (NLM
                      Chemicals) / Recombinant Proteins (NLM Chemicals) /
                      Cathepsins (NLM Chemicals) / Calpain (NLM Chemicals) /
                      Calcium (NLM Chemicals)},
      cin          = {AG Zerr / Ext UMG Zerr / AG Bonn 2 / AG Bonn 1 / AG
                      Fischer},
      ddc          = {610},
      cid          = {I:(DE-2719)1440011-1 / I:(DE-2719)5000037 /
                      I:(DE-2719)1440012 / I:(DE-2719)1410003 /
                      I:(DE-2719)1410002},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28449707},
      pmc          = {pmc:PMC5408381},
      doi          = {10.1186/s40478-017-0431-y},
      url          = {https://pub.dzne.de/record/139239},
}