{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:55:43Z","timestamp":1791190543431,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteomics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory demyelinating diseases of the CNS whose diagnosis is mainly based on clinical evidence, magnetic resonance imaging, and the analysis of cerebrospinal fluid (CSF). Current approaches provide only partial insight into disease\u2010related biological processes, thus the need for deeper characterization of CNS\u2010derived molecular signatures has emerged. Here, we applied a high\u2010resolution top\u2010down peptidomic approach in CSF from treatment na\u00efve patients with CIS, relapsing\u2013remitting multiple sclerosis (RRMS), NMOSD, and non\u2010inflammatory neurological controls. The goal was to characterize their CSF endopeptidome, unravel insights into disease\u2010associated proteolytic remodeling and molecular signatures not accessible through conventional proteomic approaches. 381 endogenous peptides were identified, including a substantial proportion of previously unreported sequences and oxidative PTMs. Quantitative analyses revealed disease\u2010associated alteration of the CSF endopeptidome. A newly characterized C\u2010terminal peptide derived from secretogranin\u20105 progressively decreased from CIS to RRMS and represented the most informative feature for discriminating patients using random forest (RF) analysis. In contrast, NMOSD patients exhibited a distinct profile characterized by widespread peptide reduction and decreased level of oxidation. Overall, these findings support the CSF endopeptidome as a biologically informative molecular layer associated with secretory pathway alteration, PTMs, and intrathecal inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance of the Study<\/jats:title>\n                    <jats:p>Top\u2010down peptidomics directly captures endogenous peptides and their native PTMs, providing information on proteolytic processing, that is lost in conventional digestion\u2010based workflows or immune\u2010based targeted approaches. In this top\u2010down exploratory study, we characterized for the first time the CSF endopeptidome of treatment\u2010na\u00efve patients with CIS, RRMS stratified by oligoclonal\u2010band (OCBs) status, NMOSD, and non\u2010inflammatory neurological controls. The results revealed disease\u2010associated patterns of granin\u2010, osteopontin\u2010, proSAAS\u2010, and fibrinogen\u2010derived peptides, especially for oxidative derivatives. A newly characterized C\u2010terminal secretogranin\u20105 peptide showed a progressive cross\u2010sectional decrease across the CIS and RRMS groups and contributed strongly to group classification, whereas NMOSD was characterized by widespread peptide depletion and a lower representation of oxidized peptide species. These findings support the CSF endopeptidome as a complementary molecular layer for investigating regulated proteolysis and redox\u2010dependent alteration in inflammatory demyelinating disorders and identify peptide candidates for future validation in independent cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pmic.70188","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:33:30Z","timestamp":1791189210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Top\u2010Down CSF Peptidomics Reveals Disease\u2010Associated Peptide Signatures and Oxidative Modifications in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder"],"prefix":"10.1002","author":[{"given":"Cristina","family":"Contini","sequence":"first","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Lorefice","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Public Health Multiple Sclerosis Center Binaghi Hospital, ASL Cagliari, University of Cagliari  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greca","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Schirru","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Zodio","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Cabras","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Olianas","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Cocco","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Public Health Multiple Sclerosis Center Binaghi Hospital, ASL Cagliari, University of Cagliari  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Manconi","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria Monserrato  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(17)30470\u20102"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3871"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028928"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(25)00270\u20104"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001729"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23137332"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20109706\u20100_12"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2026.01.017"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20103\u2010540\u201073677\u20106_6"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201600384"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1076421"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/11772719211013352"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200268"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.52033"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2018.07.019"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974\u2010022\u201002404\u20102"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517\u20106161.1995.tb02031.x"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1010933404324"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.3233\/FI\u20102010\u2010288"},{"key":"e_1_2_14_22_1","volume-title":"R: 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