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Prions Strongly Reduce NMDA Receptor S-Nitrosylation Levels at Pre-symptomatic and Terminal Stages of Prion Diseases

  • Elisa Meneghetti
  • Lisa Gasperini
  • Tommaso Virgilio
  • Fabio Moda
  • Fabrizio Tagliavini
  • Federico Benetti
  • Giuseppe LegnameEmail author
Article
  • 90 Downloads

Abstract

Prion diseases are fatal neurodegenerative disorders characterized by the cellular prion protein (PrPC) conversion into a misfolded and infectious isoform termed prion or PrPSc. The neuropathological mechanism underlying prion toxicity is still unclear, and the debate on prion protein gain- or loss-of-function is still open. PrPC participates to a plethora of physiological mechanisms. For instance, PrPC and copper cooperatively modulate N-methyl-D-aspartate receptor (NMDAR) activity by mediating S-nitrosylation, an inhibitory post-translational modification, hence protecting neurons from excitotoxicity. Here, NMDAR S-nitrosylation levels were biochemically investigated at pre- and post-symptomatic stages of mice intracerebrally inoculated with RML, 139A, and ME7 prion strains. Neuropathological aspects of prion disease were studied by histological analysis and proteinase K digestion. We report that hippocampal NMDAR S-nitrosylation is greatly reduced in all three prion strain infections in both pre-symptomatic and terminal stages of mouse disease. Indeed, we show that NMDAR S-nitrosylation dysregulation affecting prion-inoculated animals precedes the appearance of clinical signs of disease and visible neuropathological changes, such as PrPSc accumulation and deposition. The pre-symptomatic reduction of NMDAR S-nitrosylation in prion-infected mice may be a possible cause of neuronal death in prion pathology, and it might contribute to the pathology progression opening new therapeutic strategies against prion disorders.

Keywords

Prions NMDA receptor S-Nitrosylation Nitric oxide Copper Excitotoxicity 

Notes

Funding Information

This work was supported/partially supported by the Italian Ministry of Health (GR-2013-02355724 and RC) to FM, Italian Ministry of Health to FT, SISSA Intramural Funding to GL, and SISSA grant to FB (Young SISSA Scientists Research Projects 2011–2012 Scheme). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with Ethical Standards

Animal procedures were performed in accordance with European regulations (Directive 2010/63/EU) and with Italian Legislative Decree 26/2014 and were approved by the local authority veterinary service and by the Italian Ministry of Health, Directorate General for Animal Health. All efforts were made to minimize animal suffering and to reduce the number of animals used. Animal facility is licensed and inspected by the Italian Ministry of Health.

Conflict of Interests

The authors declare that they have no competing interests.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Elisa Meneghetti
    • 1
  • Lisa Gasperini
    • 1
  • Tommaso Virgilio
    • 2
  • Fabio Moda
    • 2
  • Fabrizio Tagliavini
    • 3
  • Federico Benetti
    • 1
    • 4
  • Giuseppe Legname
    • 1
    • 5
    Email author
  1. 1.Laboratory of Prion Biology, Department of NeuroscienceScuola Internazionale Superiore di Studi Avanzati (SISSA)TriesteItaly
  2. 2.Fondazione IRCCS Istituto Neurologico Carlo Besta, Unit of Neuropathology and Neurology-5MilanoItaly
  3. 3.Fondazione IRCCS Istituto Neurologico Carlo Besta, Scientific DirectorateMilanoItaly
  4. 4.ECSIN-European Center for the Sustainable Impact of NanotechnologyECAMRICERT SRLPadovaItaly
  5. 5.ELETTRA LaboratoryTriesteItaly

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