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@INPROCEEDINGS{Kaczmarczyk:145575,
      author       = {Kaczmarczyk, Lech and Jackson, Walker Scot},
      title        = {{C}aribou {P}rnp polymorphism distribution in {C}anada and
                      its impact on {CWD} pathogenesis},
      journal      = {Prion},
      volume       = {13},
      issn         = {1933-6896},
      reportid     = {DZNE-2020-00908},
      pages        = {28 - 29},
      year         = {2019},
      abstract     = {Wild reindeer in Norway were recently diagnosed withchronic
                      wasting disease (CWD) [1]. Prions from CWD-infected deer
                      were also transmissible to other reindeer inexperimental
                      settings [2,3]. Although CWD has not yetbeen reported in
                      wild reindeer (caribou) in Canada, thesestudies show that
                      they are at risk of infection. The wild-typereindeer,
                      homozygous for serine at prion protein (PrP)residue 138
                      (138SS), developed clinical disease upon oralinoculation.
                      Animals carrying at least one asparagine allele(138SN,
                      138NN) accumulated prions only in the periphery.However,
                      both genotypes were susceptible to intracerebralprion
                      inoculation [2,3]. Fallow deer are wild-type 138NNand are
                      resistant to peripheral but not intracerebral prioninfection
                      [4]. Thus, we hypothesize that the138N allele,present in
                      caribou herds in Alberta [5], alters CWD patho-genesis by
                      limiting prion transport from the periphery tothe CNS. Our
                      aim is to elucidate the mechanisms involvedin this
                      process.We extracted DNA from ±800 caribou, sequenced
                      thePrnpopen reading frame and determined the 138N
                      alleleprevalence in Canadian caribou populations.
                      Resultsshow that the 138N allele was highly prevalent in
                      theChinchaga woodland caribou population in BC $(64\%).$
                      Itwas also higher in barren-ground $(37\%)$ than in
                      otherwoodland caribou populations $(26\%).$ To analyse
                      howthe 138N allele affects CWD pathogenesis, we
                      generatedknock-in (KI) mice where the mouse PrP is replaced
                      bywild-type 138SS or 138NN cervid PrP. The KIs wereobtained
                      by injecting CRISPR/Cas9-edited C57BL6embryonic stem cells
                      (Bruce4) into wild-type blastocysts,generating chimeras, and
                      breeding progeny to homozyg-osity in a C57BL6 background.
                      PrP expression was deter-mined using western blotting and
                      qPCR. Correct PrPpost-translational modifications were
                      confirmed byPNGase-F and Endo-H digestion. We will inoculate
                      ourKIs with CWD-positive material from the
                      correspondingreindeer genotypes [1,2]. The CWD-infected
                      reindeermaterial was characterized by real-time
                      quaking-inducedconversion (RT-QuIC) and its transmissibility
                      to trans-genic mice overexpressing elk PrP (TgElk). Attack
                      rate inthe TgElks were almost $100\%,$ except for those
                      inoculatedwith 138SN lymph node material. Western blotting
                      con-firmed the presence of proteinase-K resistant PrP in
                      allterminally ill mice. Our goal is to analyse the
                      susceptibilityof KIs carrying the 138N allele to
                      intracerebral and per-ipheral prion infection. We will also
                      assess the efficiencyof prion transport from the periphery
                      to the CNS in intraperitoneally inoculated KIs. Prion strain
                      propagationwithin a host is highly dependent on its PrP
                      genotype.This study will provide insight into how the 138N
                      PrPspecifically influences CWD propagation in caribou.},
      month         = {May},
      date          = {2019-05-21},
      organization  = {PRION 2019, Edmonton (Canada), 21 May
                       2019 - 24 May 2019},
      cin          = {AG Jackson},
      ddc          = {570},
      cid          = {I:(DE-2719)1013019},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      url          = {https://pub.dzne.de/record/145575},
}