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Excitotoxicity Through NMDA Receptors Mediates Cerebellar Granule Neuron Apoptosis Induced by Prion Protein 90-231 Fragment

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Abstract

Prion diseases recognize, as a unique molecular trait, the misfolding of CNS-enriched prion protein (PrPC) into an aberrant isoform (PrPSc). In this work, we characterize the in vitro toxicity of amino-terminally truncated recombinant PrP fragment (amino acids 90-231, PrP90-231), on rat cerebellar granule neurons (CGN), focusing on glutamatergic receptor activation and Ca2+ homeostasis impairment. This recombinant fragment assumes a toxic conformation (PrP90-231TOX) after controlled thermal denaturation (1 h at 53 °C) acquiring structural characteristics identified in PrPSc (enrichment in β-structures, increased hydrophobicity, partial resistance to proteinase K, and aggregation in amyloid fibrils). By annexin-V binding assay, and evaluation of the percentage of fragmented and condensed nuclei, we show that treatment with PrP90-231TOX, used in pre-fibrillar aggregation state, induces CGN apoptosis. This effect was associated with a delayed, but sustained elevation of [Ca2+]i. Both CGN apoptosis and [Ca2+]i increase were not observed using PrP90-231 in PrPC-like conformation. PrP90-231TOX effects were significantly reduced in the presence of ionotropic glutamate receptor antagonists. In particular, CGN apoptosis and [Ca2+]i increase were largely reduced, although not fully abolished, by pre-treatment with the NMDA antagonists APV and memantine, while the AMPA antagonist CNQX produced a lower, although still significant, effect. In conclusion, we report that CGN apoptosis induced by PrP90-231TOX correlates with a sustained elevation of [Ca2+]i mediated by the activation of NMDA and AMPA receptors.

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Acknowledgments

This study has been supported by grants from Italian Ministry of University and Research (MIUR-PRIN 2008, and Accordi di Programma FIRB, Project No. RBAP11HSZS, 2011).

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Authors and Affiliations

  1. Department of Internal Medicine, Section of Pharmacology and Centre of Excellence for Biomedical Research (CEBR) School of Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy

    Stefano Thellung, Alessandro Corsaro, Valentina Villa & Tullio Florio

  2. Department of Physics, University of Genova, Genoa, Italy

    Elena Gatta, Francesca Pellistri & Mauro Robello

  3. Institute of Biophysics (IBF), National Council of Research (CNR), Genoa, Italy

    Massimo Vassalli

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  1. Stefano Thellung
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  2. Elena Gatta
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Correspondence to Tullio Florio.

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Stefano Thellung, Elena Gatta and Francesca Pellistri contributed equally to this study.

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Thellung, S., Gatta, E., Pellistri, F. et al. Excitotoxicity Through NMDA Receptors Mediates Cerebellar Granule Neuron Apoptosis Induced by Prion Protein 90-231 Fragment. Neurotox Res 23, 301–314 (2013). https://doi.org/10.1007/s12640-012-9340-9

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