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

Meneghetti, Elisa; Gasperini, Lisa; Virgilio, Tommaso; Moda, Fabio; Tagliavini, Fabrizio; Benetti, Federico; Legname, Giuseppe

doi:10.1007/s12035-019-1505-6

Cited by 16 publications

(10 citation statements)

References 75 publications

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“…One way by which PrP modulates signalling cascades is via interaction with different transmembrane partners. An inhibitory effect on excitotoxicity is mediated by binding of PrP to the NMDA receptor (Huang et al 2021 ; Khosravani et al 2008 ; Meneghetti et al 2019 ; Petit-Paitel et al 2012 ), whereas its interaction with this receptor and metabotropic glutamate receptor mGluR5 mediates toxicity upon binding of harmful protein oligomers (Hamilton et al 2015 ; Hu et al 2014 ; Resenberger et al 2011 ; Um et al 2013 ; You et al 2012 ). Binding of PrP to the 37 kDa/67 kDa laminin receptor precursor (LRP/LR) (Gauczynski et al 2001 ; Hundt et al 2001 ; Simoneau et al 2003 ) or the low-density lipoprotein receptor-related protein 1 (LRP1) (Parkyn et al 2008 ; Taylor and Hooper 2007 ) (note the similar nomenclature!)…”

Section: Further Biological Roles Influenced By Shedding or Played By...mentioning

confidence: 99%

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

et al. 2022

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The prion protein (PrP) is a broadly expressed glycoprotein linked with a multitude of (suggested) biological and pathological implications. Some of these roles seem to be due to constitutively generated proteolytic fragments of the protein. Among them is a soluble PrP form, which is released from the surface of neurons and other cell types by action of the metalloprotease ADAM10 in a process termed ‘shedding’. The latter aspect is the focus of this review, which aims to provide a comprehensive overview on (i) the relevance of proteolytic processing in regulating cellular PrP functions, (ii) currently described involvement of shed PrP in neurodegenerative diseases (including prion diseases and Alzheimer’s disease), (iii) shed PrP’s expected roles in intercellular communication in many more (patho)physiological conditions (such as stroke, cancer or immune responses), (iv) and the need for improved research tools in respective (future) studies. Deeper mechanistic insight into roles played by PrP shedding and its resulting fragment may pave the way for improved diagnostics and future therapeutic approaches in diseases of the brain and beyond.

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Section: Further Biological Roles Influenced By Shedding or Played By...mentioning

confidence: 99%

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

et al. 2022

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“…The consequent S-nitrosylation inhibits the NMDAR, leading to a reduction of the neurotoxic effect caused by its overactivation. In a subsequent study, the NMDAR S-nitrosylation levels were analyzed at pre- and post-symptomatic stages of mice intracerebrally inoculated with RML, 139A, and ME7 prion strains [81]. It was found a reduction of the levels of NMDAR S-nitrosylation at both pro- and pre-symptomatic stages, suggesting an impairment of NMDAR S-nitrosylation as a mechanism causing neuronal death in prion diseases.…”

Section: Prpc Functions Suggested By Copper Bindingmentioning

confidence: 99%

“…It was found a reduction of the levels of NMDAR S-nitrosylation at both pro- and pre-symptomatic stages, suggesting an impairment of NMDAR S-nitrosylation as a mechanism causing neuronal death in prion diseases. Therefore, the progression of excitotoxicity might be blocked by restoring NMDAR modulation and preventing neuronal loss thus opening the possibility for new therapeutic approaches against prion disorders [81]. These findings underlined the role of Cu-bound to PrP C in neuroprotective mechanisms, which could be altered by the presence of ligand that interfere with copper binding, as the case of amyloid-β (Aβ) that might mediate neuronal and synaptic injury by disrupting the normal NMDAR activity [82].…”

Section: Prpc Functions Suggested By Copper Bindingmentioning

confidence: 99%

Structural Consequences of Copper Binding to the Prion Protein

Salzano

Giachin

Legname

2019

Cells

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Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability to bind copper ions through its flexible N-terminal moiety. This review includes an overview of the structure and function of PrPC with a focus on its ability to bind copper ions. The state-of-the-art of the role of copper in both PrPC physiology and in prion pathogenesis is also discussed. Finally, we describe the structural consequences of copper binding to the PrPC structure.

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“…Compared to other post-translational modifications, S -nitrosothiols are unstable due to the lability of S - N bonds, the presence of denitrosylases and other reducing agents, such as ascorbate, and the reaction with reduced glutathione (GSH), resulting in the formation of a mixed disulfide between a protein and GSH ( S -glutathionylation) [ 5 ]. The development of methods for the analysis of S -nitrosylation of proteins [ 6 , 7 ] has made it possible to identify more than two dozen proteins, the level of S -nitrosylation of which changes in some diseases—especially in disorders of the cardiovascular, musculoskeletal, and nervous systems [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Modification of Glyceraldehyde-3-Phosphate Dehydrogenase with Nitric Oxide: Role in Signal Transduction and Development of Apoptosis

et al. 2021

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This review focuses on the consequences of GAPDH S-nitrosylation at the catalytic cysteine residue. The widespread hypothesis according to which S-nitrosylation causes a change in GAPDH structure and its subsequent binding to the Siah1 protein is considered in detail. It is assumed that the GAPDH complex with Siah1 is transported to the nucleus by carrier proteins, interacts with nuclear proteins, and induces apoptosis. However, there are several conflicting and unproven elements in this hypothesis. In particular, there is no direct confirmation of the interaction between the tetrameric GAPDH and Siah1 caused by S-nitrosylation of GAPDH. The question remains as to whether the translocation of GAPDH into the nucleus is caused by S-nitrosylation or by some other modification of the catalytic cysteine residue. The hypothesis of the induction of apoptosis by oxidation of GAPDH is considered. This oxidation leads to a release of the coenzyme NAD+ from the active center of GAPDH, followed by the dissociation of the tetramer into subunits, which move to the nucleus due to passive transport and induce apoptosis. In conclusion, the main tasks are summarized, the solutions to which will make it possible to more definitively establish the role of nitric oxide in the induction of apoptosis.

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

Cited by 16 publications

References 75 publications

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

Structural Consequences of Copper Binding to the Prion Protein

Modification of Glyceraldehyde-3-Phosphate Dehydrogenase with Nitric Oxide: Role in Signal Transduction and Development of Apoptosis

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