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@ARTICLE{Eigenbrod:139661,
      author       = {Eigenbrod, Sabina and Frick, Petra and Bertsch, Uwe and
                      Mitteregger-Kretzschmar, Gerda and Mielke, Janina and
                      Maringer, Marko and Piening, Niklas and Hepp, Alexander and
                      Daude, Nathalie and Windl, Otto and Levin, Johannes and
                      Giese, Armin and Sakthivelu, Vignesh and Tatzelt, Jörg and
                      Kretzschmar, Hans and Westaway, David},
      title        = {{S}ubstitutions of {P}r{P} {N}-terminal histidine residues
                      modulate scrapie disease pathogenesis and incubation time in
                      transgenic mice.},
      journal      = {PLOS ONE},
      volume       = {12},
      number       = {12},
      issn         = {1932-6203},
      address      = {San Francisco, California, US},
      publisher    = {PLOS},
      reportid     = {DZNE-2020-05983},
      pages        = {e0188989},
      year         = {2017},
      abstract     = {Prion diseases have been linked to impaired copper
                      homeostasis and copper induced-oxidative damage to the
                      brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to
                      cellular prion protein (PrPC) at octapeptide repeat (OR) and
                      non-OR sites within the N-terminal half of the protein but
                      information on the impact of such binding on conversion to
                      the misfolded isoform often derives from studies using
                      either OR and non-OR peptides or bacterially-expressed
                      recombinant PrP. Here we created new transgenic mouse lines
                      expressing PrP with disrupted copper binding sites within
                      all four histidine-containing OR's (sites 1-4, H60G, H68G,
                      H76G, H84G, 'TetraH>G' allele) or at site 5 (composed of
                      residues His-95 and His-110; 'H95G' allele) and monitored
                      the formation of misfolded PrP in vivo. Novel transgenic
                      mice expressing PrP(TetraH>G) at levels comparable to
                      wild-type (wt) controls were susceptible to mouse-adapted
                      scrapie strain RML but showed significantly prolonged
                      incubation times. In contrast, amino acid replacement at
                      residue 95 accelerated disease progression in corresponding
                      PrP(H95G) mice. Neuropathological lesions in terminally ill
                      transgenic mice were similar to scrapie-infected wt
                      controls, but less severe. The pattern of PrPSc deposition,
                      however, was not synaptic as seen in wt animals, but instead
                      dense globular plaque-like accumulations of PrPSc in
                      TgPrP(TetraH>G) mice and diffuse PrPSc deposition in
                      (TgPrP(H95G) mice), were observed throughout all brain
                      sections. We conclude that OR and site 5 histidine
                      substitutions have divergent phenotypic impacts and that cis
                      interactions between the OR region and the site 5 region
                      modulate pathogenic outcomes by affecting the PrP globular
                      domain.},
      keywords     = {Animals / Histidine: chemistry / Mice / Mice, Transgenic /
                      Prion Proteins: chemistry / Scrapie: pathology / Prion
                      Proteins (NLM Chemicals) / Histidine (NLM Chemicals)},
      cin          = {AG Neumann},
      ddc          = {610},
      cid          = {I:(DE-2719)1210003},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29220360},
      pmc          = {pmc:PMC5722314},
      doi          = {10.1371/journal.pone.0188989},
      url          = {https://pub.dzne.de/record/139661},
}