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 Legname

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)6035-6045
Number of pages11
JournalMolecular Neurobiology
Volume56
Issue number9
DOIs
Publication statusPublished - Sep 15 2019

Keywords

  • Copper
  • Excitotoxicity
  • Nitric oxide
  • NMDA receptor
  • Prions
  • S-Nitrosylation

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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