Vabilo na Preglov kolokvij / Invitation to the Pregl colloquium

[Brigita Pirc]

VABILO NA PREGLOV KOLOKVIJ / INVITATION TO THE PREGL COLLOQUIUM

Prof. Adriano Aguzzi
Institute of Neuropathology, University Hospital Zurich, Switzerland
adriano.aguzzi at usz.ch<mailto:adriano.aguzzi at usz.ch>
Torek / Tuesday 17. 5. 2016, ob / at 13:00
Velika predavalnica Kemijskega inštituta / Lecture Hall, National Institute of Chemistry; Hajdrihova 19, Ljubljana


PrPC function and prion toxicity

A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp‐/‐ mice. Prnp‐linked loci polymorphic between 129 and the backcrossing strain led to erroneous conclusions. We used TALEN‐mediated genome editing in fertilized mouse oocytes to create the Zurich‐3 (ZH3) Prnp‐ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of PrnpZH3/ZH3 mice failed to identify phenotypes previously described in non‐coisogenic Prnp‐/‐ mice. However, aged PrnpZH3/ZH3 mice developed a chronic demyelinating peripheral neuropathy (CDP), confirming the crucial involvement of PrPC in peripheral myelin maintenance. Neuron‐restricted PrPC expression prevents the CDP, suggesting that it acts in trans through an unidentified Schwann cell receptor. We found that the cAMP concentration in PrPC‐deficient sciatic nerves is reduced, suggesting the involvement of a G protein‐coupled receptor (GPCR). The amino‐terminal "flexible tail" (FT, residues 23‐120) of PrPC triggered a concentration‐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‐cell line abolished the FT‐induced cAMP response. A 27‐mer PrPC‐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 PrPC promotes myelin homeostasis through FT‐mediated GPCR agonism. Antibodies against the prion protein PrPC 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 PrPC, are profoundly neurotoxic, yet antibody ICSM18 was reported to be innocuous when injected into mouse brains. Both D13 and ICSM18 induced rapid, dose‐dependent, on‐target neurotoxicity. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. We posit that any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.
Vljudno vabljeni / Kindly invited!



info: Roman Jerala (roman.jerala at ki.si<mailto:roman.jerala at ki.si>)

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