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<span lang="EN-US" style="font-size:9.0pt;font-family:"Verdana","sans-serif";color:black;font-weight:normal"><o:p> </o:p></span></p>
<p class="MsoTitle" style="margin:0cm;margin-bottom:.0001pt"><span lang="EN-US" style="font-size:14.0pt;font-family:"Verdana","sans-serif";color:black;font-weight:normal">VABILO NA PREGLOV KOLOKVIJ / INVITATION TO THE PREGL COLLOQUIUM</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:black;font-weight:normal"><o:p></o:p></span></p>
<p class="MsoNormal"><b><span lang="EN-US" style="font-size:18.0pt;font-family:"Verdana","sans-serif""><o:p> </o:p></span></b></p>
<p class="MsoNormal" align="center" style="text-align:center;layout-grid-mode:char;text-autospace:none;vertical-align:baseline">
<b><span lang="EN-US" style="font-size:18.0pt;font-family:"Verdana","sans-serif"">Prof. Adriano Aguzzi<o:p></o:p></span></b></p>
<p class="MsoNormal" align="center" style="text-align:center"><span lang="EN-US" style="font-size:12.0pt;font-family:"Verdana","sans-serif"">Institute of Neuropathology, University Hospital Zurich, Switzerland<o:p></o:p></span></p>
<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><span lang="EN-US" style="font-size:12.0pt;line-height:150%;font-family:"Verdana","sans-serif""><a href="mailto:adriano.aguzzi@usz.ch">adriano.aguzzi@usz.ch</a></span><b><span lang="EN-US" style="font-size:8.0pt;line-height:150%;font-family:"Verdana","sans-serif""><o:p></o:p></span></b></p>
<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><b><span lang="EN-US" style="font-size:16.0pt;line-height:150%;font-family:"Verdana","sans-serif"">Torek / Tuesday 17. 5. 2016, ob / at 13:00
<o:p></o:p></span></b></p>
<h6 style="mso-margin-top-alt:0cm;margin-right:0cm;margin-bottom:6.0pt;margin-left:0cm">
<b><span lang="EN-US" style="font-size:12.0pt;font-family:"Verdana","sans-serif"">Velika predavalnica Kemijskega inštituta / Lecture Hall, National Institute of Chemistry; Hajdrihova 19, Ljubljana<o:p></o:p></span></b></h6>
<p class="EndNoteBibliography" style="margin-bottom:0cm;margin-bottom:.0001pt"><span lang="EN-US" style="font-size:9.0pt;font-family:"Verdana","sans-serif";color:#660066"><o:p> </o:p></span></p>
<p class="MsoNormal" align="center" style="text-align:center;layout-grid-mode:char">
<b><span lang="EN-US" style="font-size:16.0pt;font-family:"Verdana","sans-serif";color:#792D4C;mso-fareast-language:EN-US">PrP<sup>C</sup> function and prion toxicity<o:p></o:p></span></b></p>
<p class="MsoNormal" align="center" style="text-align:center;layout-grid-mode:char">
<span lang="EN-US" style="font-size:12.0pt;color:black;mso-fareast-language:JA"><o:p> </o:p></span></p>
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<span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">A plethora of functions have been ascribed to PrP<sup>C</sup> based on phenotypes of
<i>Prnp</i></span><i><sup><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span></sup></i><i><sup><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">/</span></sup></i><i><sup><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span></sup></i><i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">
</span></i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">mice.
<i>Prnp</i></span><i><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span></i><i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">linked
</span></i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">loci polymorphic between 129 and the backcrossing strain led to erroneous conclusions. We used TALEN</span><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">mediated
genome editing in fertilized mouse oocytes to create the Zurich</span><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">3 (ZH3)
<i>Prnp</i></span><i><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span></i><i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">ablated
</span></i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of
<i>Prnp<sup>ZH3/ZH3</sup> </i>mice failed to identify phenotypes previously described in non</span><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">coisogenic
<i>Prnp</i></span><i><sup><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span></sup></i><i><sup><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">/</span></sup></i><i><sup><span lang="EN-US" style="font-family:"Noteworthy Light";mso-fareast-language:EN-US">‐</span></sup></i><i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">
</span></i><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">mice. However, aged
<i>Prnp<sup>ZH3/ZH3</sup> </i>mice developed a chronic demyelinating peripheral neuropathy (CDP), confirming the crucial involvement of PrP<sup>C</sup> in peripheral myelin maintenance.
<span style="color:#262626">Neuron</span></span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">restricted
PrP<sup>C</sup> expression prevents the CDP, suggesting that it acts in trans through an unidentified Schwann cell receptor. We found that the cAMP concentration in PrP<sup>C</sup></span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">deficient
sciatic nerves is reduced, suggesting the involvement of a G protein</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">coupled
receptor (GPCR). The amino</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">terminal "flexible
tail" (FT, residues 23</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">120) of
</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">PrP<sup>C</sup>
<span style="color:#262626">triggered a concentration</span></span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">dependent
cAMP increase in primary Schwann cells and in Hek293T cells overexpressing a specific GPCR. In contrast, naïve Hek293T cells and Hek293T cells expressing several other GPCRs did not react to the FT, and ablation of this GPCR from a Schwann</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">cell
line abolished the FT</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">induced cAMP response.
A 27</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">mer PrP<sup>C</sup></span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">derived
peptide sufficed to induce a cAMP response in cells and mice, and improved myelination in hypomorphic zebrafish mutants lacking the orthologous GCPR receptor.. We conclude that
</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">PrP<sup>C</sup>
<span style="color:#262626">promotes myelin homeostasis through FT</span></span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">mediated
GPCR agonism.</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US">
<span style="color:#262626">Antibodies against the prion protein PrP<sup>C</sup> can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. We have reported that several antibodies against
certain epitopes of PrP<sup>C</sup>, are profoundly neurotoxic, yet antibody ICSM18 was reported to be innocuous when injected into mouse brains. Both D13 and ICSM18 induced rapid, dose</span></span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">dependent,
on</span><span lang="EN-US" style="font-family:"Noteworthy Light";color:#262626;mso-fareast-language:EN-US">‐</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";color:#262626;mso-fareast-language:EN-US">target neurotoxicity. No such toxicity
was found when antibodies against the flexible tail of PrP<sup>C</sup> were administered. We posit that any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.</span><span lang="EN-US" style="font-family:"Verdana","sans-serif";mso-fareast-language:EN-US"><o:p></o:p></span></p>
<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><b><span lang="EN-US" style="font-size:14.0pt;line-height:150%;font-family:"Verdana","sans-serif"">Vljudno vabljeni / Kindly invited!<o:p></o:p></span></b></p>
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<p class="MsoFooter" align="center" style="text-align:center"><span lang="IT" style="font-size:11.0pt;font-family:"Verdana","sans-serif"">info:
</span><span lang="EN-GB" style="font-family:"Verdana","sans-serif";mso-fareast-language:SL">Roman Jerala (<a href="mailto:roman.jerala@ki.si">roman.jerala@ki.si</a>)</span><span lang="IT" style="font-size:11.0pt;font-family:"Verdana","sans-serif""><o:p></o:p></span></p>
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