{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:46:40Z","timestamp":1791352000931,"version":"4.3.1"},"reference-count":42,"publisher":"SAGE Publications","issue":"9","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Several neurodegenerative disorders show alterations in glutamatergic synapses and increased susceptibility to excitotoxicity. Mounting evidence suggests a central role for the cellular prion protein (PrP\n                    <jats:sup>C<\/jats:sup>\n                    ) in neuroprotection. Therefore, the loss of PrP\n                    <jats:sup>C<\/jats:sup>\n                    function occurring in prion disorders may contribute to the disease progression and neurodegeneration. Indeed, PrP\n                    <jats:sup>C<\/jats:sup>\n                    modulates\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -methyl-\n                    <jats:sc>d<\/jats:sc>\n                    -aspartate receptors (NMDAR), thus preventing cell death. In this study, we show that PrP\n                    <jats:sup>C<\/jats:sup>\n                    and copper cooperatively inhibit NMDAR through S-nitrosylation, a post-translational modification resulting from the chemical reaction of nitric oxide (NO) with cysteines.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    Comparing wild-type\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    ) and PrP\n                    <jats:sup>C<\/jats:sup>\n                    knockout (\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    ) mouse hippocampi, we found that GluN1 and GluN2A S-nitrosylation decrease in\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    . Using organotypic hippocampal cultures, we found that copper chelation decreases NMDAR S-nitrosylation in\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    but not in\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    . This suggests that PrP\n                    <jats:sup>C<\/jats:sup>\n                    requires copper to support the chemical reaction between NO and thiols. We explored PrP\n                    <jats:sup>C<\/jats:sup>\n                    -Cu neuroprotective role by evaluating neuron susceptibility to excitotoxicity in\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    and\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    cultures. We found that (i) PrP\n                    <jats:sup>C<\/jats:sup>\n                    -Cu modulates GluN2A-containing NMDAR, those inhibited by S-nitrosylation; (ii) PrP\n                    <jats:sup>C<\/jats:sup>\n                    and copper are interdependent to protect neurons from insults; (iii) neuronal NO synthase inhibition affects susceptibility in wild-type but not in\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    , while (iv) the addition of a NO donor enhances\n                    <jats:italic toggle=\"yes\">Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    neurons survival.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation and Conclusions:<\/jats:italic>\n                    <\/jats:bold>\n                    Our results show that PrP\n                    <jats:sup>C<\/jats:sup>\n                    and copper support NMDAR S-nitrosylation and cooperatively exert neuroprotection. In addition to NMDAR, PrP\n                    <jats:sup>C<\/jats:sup>\n                    may also favor the S-nitrosylation of other proteins. Therefore, this mechanism may be investigated in the context of the different cellular processes in which PrP\n                    <jats:sup>C<\/jats:sup>\n                    is involved.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                    22, 772\u2013784.\n                  <\/jats:p>","DOI":"10.1089\/ars.2014.6032","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T17:50:04Z","timestamp":1418147404000},"page":"772-784","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":128,"title":["Prion Protein and Copper Cooperatively Protect Neurons by Modulating NMDA Receptor Through S-nitrosylation"],"prefix":"10.1177","volume":"22","author":[{"given":"Lisa","family":"Gasperini","sequence":"first","affiliation":[{"name":"Scuola Internazionale Superiore di Studi Avanzati (SISSA)","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Meneghetti","sequence":"additional","affiliation":[{"name":"Scuola Internazionale Superiore di Studi Avanzati (SISSA)","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Pastore","sequence":"additional","affiliation":[{"name":"Scuola Internazionale Superiore di Studi Avanzati (SISSA)","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Benetti","sequence":"additional","affiliation":[{"name":"Scuola Internazionale Superiore di Studi Avanzati (SISSA)","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Legname","sequence":"additional","affiliation":[{"name":"Scuola Internazionale Superiore di Studi Avanzati (SISSA)","place":["Italy"]},{"name":"ELETTRA - Sincrotrone Trieste S.C.p.A, AREA Science Park","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2015,3,20]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.31.060407.125620"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2010.05.008"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22357"},{"key":"e_1_3_3_5_2","first-page":"5","article-title":"Studies of nitric oxide interaction with mono- and dinuclear copper(II) complexes of prion protein bis-octarepeat fragments","volume":"380","author":"Bonomo RP","year":"2008","unstructured":"Bonomo RP, , Pappalardo G, , Rizzarelli E, , Tabbi G, , and Vagliasindi LI. Studies of nitric oxide interaction with mono- and dinuclear copper(II) complexes of prion protein bis-octarepeat fragments. Dalton Trans, 380:5\u20133816, 2008.","journal-title":"Dalton Trans"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/37783"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4149-12.2013"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/71090"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi300233n"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1792-10.2010"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.1.110304.100218"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(03)00028-5"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004410051036"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(97)01122-3"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1085"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2012.08.014"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2911"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1569"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/stke.2001.86.pl1"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.4161\/pri.3.4.9980"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021807"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200711002"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00048.2003"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(02)02245-2"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja2045259"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.6.2403"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-002-1040-6"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbrainres.2004.08.004"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.3.202"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300394200"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1994.74.3.723"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0029(20000701)50:1<58::AID-JEMT9>3.0.CO;2-5"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.10.6324"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105173442006"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21215"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1998.00258.x"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3699-04.2005"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605390103"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.04.002"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6371-11.2012"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1110789109"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.482000"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.82"}],"container-title":["Antioxidants &amp; Redox Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/ars.2014.6032","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/ars.2014.6032","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/ars.2014.6032","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:53:00Z","timestamp":1777377180000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/ars.2014.6032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3]]},"references-count":42,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2015,3]]}},"alternative-id":["10.1089\/ars.2014.6032"],"URL":"https:\/\/doi.org\/10.1089\/ars.2014.6032","relation":{},"ISSN":["1523-0864","1557-7716"],"issn-type":[{"value":"1523-0864","type":"print"},{"value":"1557-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3]]}}}