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@PHDTHESIS{Wsten:144823,
      author       = {Wüsten, Annick},
      title        = {{E}in zellbasierter {B}iolumineszenzassay zur
                      {U}ntersuchung der {D}imerisierung und {A}ggregation des
                      {P}rionproteins},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      address      = {Bonn},
      reportid     = {DZNE-2020-00265},
      pages        = {92 pages : illustrations},
      year         = {2017},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2017},
      abstract     = {Prion diseases like Creutzfeldt-Jakob disease (CJD) are
                      fatal neurodegenerative disorders that are triggered by
                      misfolding of the cellular prion protein (PrPC) to an
                      infectious isoform rich in β-sheet structure termed PrPSc.
                      There are evidence that PrPC possibly forms dimers
                      indicating that dimerization of PrPC may be an essential
                      intermediate step for the formation of PrPSc aggregates upon
                      infection.To study PrP dimerization and PrP aggregation upon
                      infection, a bimolecular complementation assay was developed
                      using RK13 cells that lack endogenous PrP expression and
                      stably expressed two fusion constructs between PrP and each
                      half of split Gaussia luciferase. In these cells
                      bioluminescence only occured when PrP dimerized or
                      aggregated and the two split luciferase halves complemented
                      each other.Using a panel of eight antibodies directed
                      against different PrP domains, the central domain of PrPC
                      was identified to be critical for dimerization.Unlike normal
                      brain homogenate infection of RK13 cells with brain
                      homogenates from diseased animals containing six different
                      mouse-adapted prion strains, RML, 22L, ME7, 87V, 79A, and
                      22A, lead to an increase in bioluminescence. In contrast,
                      treatment of chronically infected but not uninfected RK13
                      cells with the anti-prion compound quinacrine reduced
                      bioluminescence.Finally, a compound-screening with a
                      compound library including 1650 bioactive compounds based on
                      the bimolecular complementation assay identified JTC-801 as
                      one compound that inhibited PrPC-dimerization. Treatment of
                      ScN2a cells with JTC-801 reduced PrPSc levels in these cells
                      at nanomolar concentrations.Overall, these results showed
                      that PrPC clearly dimerizes in cells and that prion
                      infection led to increased bioluminescence in the newly
                      developed bimolecular complementation assay. The
                      identification of JTC-801 as a bioactive compounds that
                      inhibited PrPC-dimerization and reduced PrPSc-levels in
                      ScN2a cells at nanomolar concentrations suggested that PrPC
                      dimerization may be a critical step in the conversion
                      process of PrPC to PrPSc.},
      cin          = {AG Tamgüney},
      cid          = {I:(DE-2719)1013022},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5n-48485},
      url          = {https://pub.dzne.de/record/144823},
}