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Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS)

German Society for Neuropathology and Neuroanatomy

22.09.-24.09.2016, Hamburg

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Depicting the role of the FT functional domains in antiprion mediated neurodegeneration

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  • presenting/speaker Regina Reimann - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Ahmet Varol - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Lisa Caflisch - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Mario Hermann - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Simone Hornemann - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Assunta Senatore - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Vijay Chandrasekar - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Melanie Einsiedler - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Mario Nuvolone - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland
  • Bernard Schneider - Ecole Polytechnique Fédéral de Lausanne, Brain Mind Institute, Lausanne, Switzerland
  • Adriano Aguzzi - Institute of Neuropathology / UniversityHospital Zurich, Zürich, Switzerland

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. Scandinavian Neuropathological Society. Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS). Hamburg, 22.-24.09.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. Doc16dgnnP18

doi: 10.3205/16dgnn26, urn:nbn:de:0183-16dgnn262

Published: September 14, 2016

© 2016 Reimann et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Neurodegeneration is one of the central pathological hallmarks of fatal transmissible spongiform encephalopathy (TSE) affecting humans and animals. Prions represent the causative infectious agent in TSE, which are associated with PrPSC, a pathological conformer of the cellular prion protein (PrPC). The expression of the normal ubiquitously expressed PrPC is a prerequisite for prion induced neurodegeneration [1], [2] and for the propagation of PrPSC [3], [4]. Therefore, one of the first-line targets towards the development of a curative treatment is PrPC, which is encoded by Prnp and contains a globular domain (GD) hinged to an amino-proximal tail (FT, amino-acids 23-125) [5]. Neurotoxicity induced by antiprion antibodies triggers converging pathways as in bona fide TSE [6] and enables the identification of the FT as the mediator of neurotoxicity [7]. In order to identify well-defined therapeutic targets, we now address the relation between the known functional domains of the FT and its pathological function.

In order to investigate the role of FT’s different functional domains in the mediation of neurotoxicity, we assembled AAV with a bicistronic constructs allowing for the expression of unaltered or differently selectively point-mutated PrPC in cerebellar organotypic slice culture (COCS, Figure 1 [Fig. 1]). While PrP deficient mice (PrnpZH3/ZH3) are resistant towards antiprion antibody mediated neurotoxicity, we could monitor a loss of NeonGreen over time in Purkinje cells transfected with unaltered PrPC when treated with the neurotoxic FabPOM19 (Figure 2 A,B [Fig. 2]). This effect was blocked when FabPOM19 was pre-incubated with molar excesses of its cognate antigen. In line with our previous study, antibody mediated neurotoxicity is not restored in PrnpZH3/ZH3 COCS if the deletion mutant PrPΔ32-93 is expressed, which lacks larger part of the aminoterminus including the octarepeat region [7]. In contrast, a restoration was found in all mutants tested to date, which harbored point mutations in either the octarepeat or the SH3 domain (Figure 2C [Fig. 2]).

Outline

References

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