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@ARTICLE{Mehra:271073,
      author       = {Mehra, Surabhi and Bourkas, Matthew Ec and Kaczmarczyk,
                      Lech and Stuart, Erica and Arshad, Hamza and Griffin,
                      Jennifer K and Frost, Kathy L and Walsh, Daniel J and
                      Supattapone, Surachai and Booth, Stephanie A and Jackson,
                      Walker Scot and Watts, Joel C},
      title        = {{C}onvergent generation of atypical prions in knockin mouse
                      models of genetic prion disease.},
      journal      = {The journal of clinical investigation},
      volume       = {134},
      number       = {15},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DZNE-2024-00945},
      pages        = {e176344},
      year         = {2024},
      abstract     = {Most cases of human prion disease arise due to spontaneous
                      misfolding of WT or mutant prion protein, yet recapitulating
                      this event in animal models has proven challenging. It
                      remains unclear whether spontaneous prion generation can
                      occur within the mouse lifespan in the absence of protein
                      overexpression and how disease-causing mutations affect
                      prion strain properties. To address these issues, we
                      generated knockin mice that express the misfolding-prone
                      bank vole prion protein (BVPrP). While mice expressing WT
                      BVPrP (I109 variant) remained free from neurological
                      disease, a subset of mice expressing BVPrP with mutations
                      (D178N or E200K) causing genetic prion disease developed
                      progressive neurological illness. Brains from spontaneously
                      ill knockin mice contained prion disease-specific
                      neuropathological changes as well as atypical
                      protease-resistant BVPrP. Moreover, brain extracts from
                      spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice
                      exhibited prion seeding activity and transmitted disease to
                      mice expressing WT BVPrP. Surprisingly, the properties of
                      the D178N- and E200K-mutant prions appeared identical before
                      and after transmission, suggesting that both mutations guide
                      the formation of a similar atypical prion strain. These
                      findings imply that knockin mice expressing mutant BVPrP
                      spontaneously develop a bona fide prion disease and that
                      mutations causing prion diseases may share a uniform initial
                      mechanism of action.},
      keywords     = {Animals / Mice / Prion Diseases: genetics / Prion Diseases:
                      pathology / Prion Diseases: metabolism / Gene Knock-In
                      Techniques / Disease Models, Animal / Mice, Transgenic /
                      Prion Proteins: genetics / Prion Proteins: metabolism /
                      Brain: metabolism / Brain: pathology / Mutation, Missense /
                      Humans / Arvicolinae: genetics / Arvicolinae: metabolism /
                      Amino Acid Substitution / Prions: genetics / Prions:
                      metabolism / Protein Folding / Neurodegeneration (Other) /
                      Neuroscience (Other) / Prions (Other) / Prion Proteins (NLM
                      Chemicals) / Prions (NLM Chemicals)},
      cin          = {AG Jackson},
      ddc          = {610},
      cid          = {I:(DE-2719)1013019},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39087478},
      pmc          = {pmc:PMC11291267},
      doi          = {10.1172/JCI176344},
      url          = {https://pub.dzne.de/record/271073},
}