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@PHDTHESIS{Hornberger:269355,
      author       = {Hornberger, Annika},
      title        = {{T}he yeast prion domain {S}up35 {NM} models features of
                      human neurodegenerative diseases in vivo},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      publisher    = {Universitäts- und Landesbibliothek Bonn},
      reportid     = {DZNE-2024-00523},
      pages        = {97 p.},
      year         = {2024},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2024},
      abstract     = {In neurodegenerative diseases, such as prion diseases and
                      Alzheimer’s disease, disease-associated proteins misfold
                      and form amyloid deposits that progressively invade the CNS,
                      leading to severe neurodegeneration. Accumulating evidence
                      suggests that amyloid proteins propagate in a prion-like,
                      self-perpetuating manner, but the mechanism of aggregate
                      multiplication in mammals remains unclear. Amyloid deposits
                      are associated with neurodegeneration and can induce a toxic
                      gain-of-function or loss-of-function phenotype. Yet, the
                      contribution of both effects to neurodegeneration is not
                      fully understood. Surprisingly, the same pathogenic protein
                      can aggregate into different structural variants that,
                      similar to prion strains, may cause heterogenous clinical
                      symptoms. However, how the amyloid structure can influence
                      disease progression needs to be elucidated. Previously, our
                      group established the NM-HA mouse model that expresses the
                      hemagglutinin-tagged prion domain NM of the Saccharomyces
                      cerevisiae prion Sup35 that behaves like a prion in
                      mammalian cells. As NM does not possess a cellular function
                      in mammals, it can be used to study the gain-of-function of
                      protein aggregates in the absence of loss-of-function
                      effects. In this project, we used the NM-HA mouse line to
                      investigate the ability of fibril-induced NM-HA aggregates
                      to propagate in the mammalian brain, and thus to model human
                      prion-like proteins. Additionally, we tested if the
                      gain-of-function of intracellular NM-HA aggregates can cause
                      neurodegeneration and compared the disease pathogenesis
                      induced by two different NM fibril conformers. Here we show
                      that the intracranial injection of NM fibrils into NM-HA
                      animals induces progressive NM-HA aggregation, demonstrating
                      that yeast NM prions can replicate in mice. Interestingly,
                      our data points to the involvement of the chaperone
                      valosin-containing protein (VCP) as potential NM prion
                      disaggregase in this process. NM-HA aggregates seeded by the
                      NM fibril variants spread from the hippocampus to similar
                      neuroanatomically connected regions, with striking
                      similarity to pathologies observed in wildtype mice
                      challenged with disease-associated protein aggregates.
                      Fibril-injected animals develop mild cognitive decline,
                      likely caused by neuronal loss in hippocampal subregions
                      with prominent NM-HA deposition. Remarkably,
                      neurodegeneration is accompanied by local microgliosis and
                      astrogliosis. Hence, a non-mammalian and non-disease-related
                      protein is able to cause neurodegeneration upon aggregation
                      in mice, likely via a neurotoxic gain-of-function effect. As
                      fibril-injected NM-HA mice recapitulate key aspects of the
                      pathogenesis of human neurodegenerative disorders, our data
                      argue that mechanisms underlying intracellular amyloid
                      fragmentation, dissemination, and toxicity might be shared
                      between amyloidogenic proteins.},
      keywords     = {Sup35 (Other) / NM (Other) / Prion (Other) / Ausbreitung
                      (Other) / Neurodegeneration (Other) / Maus (Other) / ddc:500
                      (Other) / ddc:570 (Other) / ddc:610 (Other)},
      cin          = {AG Vorberg},
      cid          = {I:(DE-2719)1013004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)11},
      urn          = {https://nbn-resolving.org/urn:nbn:de:hbz:5-76077},
      urn          = {nbn:de:hbz:5-76077},
      urn          = {urn:nbn:de:hbz:5-76077},
      url          = {https://pub.dzne.de/record/269355},
}