{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:29:15Z","timestamp":1791286155390,"version":"4.1.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Stiftelsen Kristian Gerhard Jebsen,Norway"},{"DOI":"10.13039\/501100005036","name":"Universitetet i Bergen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005036","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010586","name":"Haukeland\u00a0Universitetssjukehus","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["288164"],"award-info":[{"award-number":["288164"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["288164"],"award-info":[{"award-number":["288164"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","award":["HV911866"],"award-info":[{"award-number":["HV911866"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Two pathophysiological different experimental models for multiple sclerosis were analyzed in parallel using quantitative proteomics in attempts to discover protein alterations applicable as diagnostic-, prognostic-, or treatment targets in human disease. The cuprizone model reflects de- and remyelination in multiple sclerosis, and the experimental autoimmune encephalomyelitis (EAE, MOG1-125) immune-mediated events. The frontal cortex, peripheral to severely inflicted areas in the CNS, was dissected and analyzed. The frontal cortex had previously not been characterized by proteomics at different disease stages, and novel protein alterations involved in protecting healthy tissue and assisting repair of inflicted areas might be discovered. Using TMT-labelling and mass spectrometry, 1871 of the proteins quantified overlapped between the two experimental models, and the fold change compared to controls was verified using label-free proteomics. Few similarities in frontal cortex between the two disease models were observed when regulated proteins and signaling pathways were compared. Legumain and C1Q complement proteins were among the most upregulated proteins in cuprizone and hemopexin in the EAE model. Immunohistochemistry showed that legumain expression in post-mortem multiple sclerosis brain tissue (n\u2009=\u200919) was significantly higher in the center and at the edge of white matter active and chronic active lesions. Legumain was associated with increased lesion activity and might be valuable as a drug target using specific inhibitors as already suggested for Parkinson\u2019s and Alzheimer\u2019s disease. Cerebrospinal fluid levels of legumain, C1q and hemopexin were not significantly different between multiple sclerosis patients, other neurological diseases, or healthy controls.<\/jats:p>","DOI":"10.1038\/s41598-021-86191-5","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T10:03:41Z","timestamp":1617098621000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis"],"prefix":"10.1038","volume":"11","author":[{"given":"Eystein","family":"Oveland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Intakhar","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhild Reehorst","family":"Lereim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Cathrine","family":"Kroksveen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Barsnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Guldbrandsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjell-Morten","family":"Myhr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"B\u00f8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frode S.","family":"Berven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stig","family":"Wergeland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"86191_CR1","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","volume":"372","author":"A Compston","year":"2008","unstructured":"Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502\u20131517 (2008).","journal-title":"Lancet"},{"key":"86191_CR2","doi-asserted-by":"publisher","first-page":"1800335","DOI":"10.1002\/pmic.201800335","volume":"19","author":"V Singh","year":"2019","unstructured":"Singh, V., Tripathi, A. & Dutta, R. Proteomic approaches to decipher mechanisms underlying pathogenesis in multiple sclerosis patients. Proteomics 19, 1800335. https:\/\/doi.org\/10.1002\/pmic.201800335 (2019).","journal-title":"Proteomics"},{"key":"86191_CR3","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nrneurol.2015.173","volume":"11","author":"CE Teunissen","year":"2015","unstructured":"Teunissen, C. E., Malekzadeh, A., Leurs, C., Bridel, C. & Killestein, J. Body fluid biomarkers for multiple sclerosis\u2014The long road to clinical application. Nat. Rev. Neurol. 11, 585\u2013596. https:\/\/doi.org\/10.1038\/nrneurol.2015.173 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"86191_CR4","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1007\/s12031-010-9354-9","volume":"42","author":"SR Werner","year":"2010","unstructured":"Werner, S. R. et al. Proteomic analysis of demyelinated and remyelinating brain tissue following dietary cuprizone administration. J. Mol. Neurosci. (MN) 42, 210\u2013225. https:\/\/doi.org\/10.1007\/s12031-010-9354-9 (2010).","journal-title":"J. Mol. Neurosci. (MN)"},{"key":"86191_CR5","doi-asserted-by":"publisher","first-page":"e7624","DOI":"10.1371\/journal.pone.0007624","volume":"4","author":"RA Linker","year":"2009","unstructured":"Linker, R. A. et al. Proteome profiling in murine models of multiple sclerosis: Identification of stage specific markers and culprits for tissue damage. PLoS ONE 4, e7624. https:\/\/doi.org\/10.1371\/journal.pone.0007624 (2009).","journal-title":"PLoS ONE"},{"key":"86191_CR6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1601277","author":"SL Hauser","year":"2016","unstructured":"Hauser, S. L. et al. Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N. Engl. J. Med. https:\/\/doi.org\/10.1056\/NEJMoa1601277 (2016).","journal-title":"N. Engl. J. Med."},{"key":"86191_CR7","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1002\/1521-4141(200207)32:7<1905::AID-IMMU1905>3.0.CO;2-L","volume":"32","author":"JA Lyons","year":"2002","unstructured":"Lyons, J. A., Ramsbottom, M. J. & Cross, A. H. Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein. Eur. J. Immunol. 32, 1905\u20131913. https:\/\/doi.org\/10.1002\/1521-4141(200207)32:7%3c1905::AID-IMMU1905%3e3.0.CO;2-L (2002).","journal-title":"Eur. J. Immunol."},{"key":"86191_CR8","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1177\/1352458514524086","volume":"20","author":"JT Mony","year":"2014","unstructured":"Mony, J. T., Khorooshi, R. & Owens, T. MOG extracellular domain (p1\u2013125) triggers elevated frequency of CXCR3+ CD4+ Th1 cells in the CNS of mice and induces greater incidence of severe EAE. Mult. Scler. 20, 1312\u20131321. https:\/\/doi.org\/10.1177\/1352458514524086 (2014).","journal-title":"Mult. Scler."},{"key":"86191_CR9","first-page":"A387","volume":"76","author":"S Wergeland","year":"2011","unstructured":"Wergeland, S. et al. Dietary vitamin D3 supplement reduces demyelination in the cuprizone model. Neurology 76, A387\u2013A387 (2011).","journal-title":"Neurology"},{"key":"86191_CR10","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1111\/j.1600-0463.2012.02882.x","volume":"120","author":"S Wergeland","year":"2012","unstructured":"Wergeland, S., Torkildsen, \u00d8., Myhr, K. M., M\u00f8rk, S. J. & B\u00f8, L. The cuprizone model: Regional heterogeneity of pathology. APMIS 120, 648\u2013657. https:\/\/doi.org\/10.1111\/j.1600-0463.2012.02882.x (2012).","journal-title":"APMIS"},{"key":"86191_CR11","doi-asserted-by":"publisher","first-page":"5338","DOI":"10.1021\/pr3005666","volume":"11","author":"E Oveland","year":"2012","unstructured":"Oveland, E. et al. Proteomic evaluation of inflammatory proteins in rat spleen interstitial fluid and lymph during LPS-induced systemic inflammation reveals increased levels of ADAMST1. J. Proteome Res. 11, 5338\u20135349. https:\/\/doi.org\/10.1021\/pr3005666 (2012).","journal-title":"J. Proteome Res."},{"key":"86191_CR12","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1002\/pmic.201000595","volume":"11","author":"M Vaudel","year":"2011","unstructured":"Vaudel, M., Barsnes, H., Berven, F. S., Sickmann, A. & Martens, L. SearchGUI: An open-source graphical user interface for simultaneous OMSSA and X!Tandem searches. Proteomics 11, 996\u2013999. https:\/\/doi.org\/10.1002\/pmic.201000595 (2011).","journal-title":"Proteomics"},{"key":"86191_CR13","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/nbt.3109","volume":"33","author":"M Vaudel","year":"2015","unstructured":"Vaudel, M. et al. PeptideShaker enables reanalysis of MS-derived proteomics data sets. Nat. Biotechnol. 33, 22\u201324. https:\/\/doi.org\/10.1038\/nbt.3109 (2015).","journal-title":"Nat. Biotechnol."},{"key":"86191_CR14","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/0165-5728(94)90075-2","volume":"51","author":"L B\u00f8","year":"1994","unstructured":"B\u00f8, L. et al. Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J. Neuroimmunol. 51, 135\u2013146 (1994).","journal-title":"J. Neuroimmunol."},{"key":"86191_CR15","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1093\/jnen\/62.7.723","volume":"62","author":"L B\u00f8","year":"2003","unstructured":"B\u00f8, L., Vedeler, C. A., Nyland, H. I., Trapp, B. D. & M\u00f8rk, S. J. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J. Neuropathol. Exp. Neurol. 62, 723\u2013732 (2003).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"86191_CR16","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1212\/WNL.0b013e3181c47cc2","volume":"73","author":"CE Teunissen","year":"2009","unstructured":"Teunissen, C. E. et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73, 1914\u20131922. https:\/\/doi.org\/10.1212\/WNL.0b013e3181c47cc2 (2009).","journal-title":"Neurology"},{"key":"86191_CR17","doi-asserted-by":"publisher","unstructured":"Cox, J. & Mann, M. 1D and 2D annotation enrichment: A statistical method integrating quantitative proteomics with complementary high-throughput data. BMC Bioinform. 13 Suppl 16, S12, https:\/\/doi.org\/10.1186\/1471-2105-13-S16-S12 (2012).","DOI":"10.1186\/1471-2105-13-S16-S12"},{"key":"86191_CR18","doi-asserted-by":"publisher","first-page":"W169","DOI":"10.1093\/nar\/gkm415","volume":"35","author":"DW Huang","year":"2007","unstructured":"Huang, D. W. et al. DAVID bioinformatics resources: Expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35, W169-175. https:\/\/doi.org\/10.1093\/nar\/gkm415 (2007).","journal-title":"Nucleic Acids Res."},{"key":"86191_CR19","doi-asserted-by":"publisher","first-page":"D109","DOI":"10.1093\/nar\/gkr988","volume":"40","author":"M Kanehisa","year":"2012","unstructured":"Kanehisa, M., Goto, S., Sato, Y., Furumichi, M. & Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 40, D109-114. https:\/\/doi.org\/10.1093\/nar\/gkr988 (2012).","journal-title":"Nucleic Acids Res."},{"key":"86191_CR20","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1093\/bioinformatics\/btq710","volume":"27","author":"D Baron","year":"2011","unstructured":"Baron, D. et al. MADGene: Retrieval and processing of gene identifier lists for the analysis of heterogeneous microarray datasets. Bioinformatics 27, 725\u2013726. https:\/\/doi.org\/10.1093\/bioinformatics\/btq710 (2011).","journal-title":"Bioinformatics"},{"key":"86191_CR21","doi-asserted-by":"publisher","first-page":"3152","DOI":"10.1074\/mcp.M114.038554","volume":"13","author":"A Guldbrandsen","year":"2014","unstructured":"Guldbrandsen, A. et al. In-depth characterization of the cerebrospinal fluid (CSF) proteome displayed through the CSF proteome resource (CSF-PR). Mol. Cell. Proteom. (MCP) 13, 3152\u20133163. https:\/\/doi.org\/10.1074\/mcp.M114.038554 (2014).","journal-title":"Mol. Cell. Proteom. (MCP)"},{"key":"86191_CR22","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/nbt.2839","volume":"32","author":"JA Vizcaino","year":"2014","unstructured":"Vizcaino, J. A. et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat. Biotechnol. 32, 223\u2013226. https:\/\/doi.org\/10.1038\/nbt.2839 (2014).","journal-title":"Nat. Biotechnol."},{"key":"86191_CR23","doi-asserted-by":"publisher","first-page":"D1063","DOI":"10.1093\/nar\/gks1262","volume":"41","author":"JA Vizcaino","year":"2013","unstructured":"Vizcaino, J. A. et al. The PRoteomics IDEntifications (PRIDE) database and associated tools: Status in 2013. Nucleic Acids Res. 41, D1063-1069. https:\/\/doi.org\/10.1093\/nar\/gks1262 (2013).","journal-title":"Nucleic Acids Res."},{"key":"86191_CR24","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1523\/JNEUROSCI.4317-05.2006","volume":"26","author":"D Brockschnieder","year":"2006","unstructured":"Brockschnieder, D., Sabanay, H., Riethmacher, D. & Peles, E. Ermin, a myelinating oligodendrocyte-specific protein that regulates cell morphology. J. Neurosci. 26, 757\u2013762. https:\/\/doi.org\/10.1523\/JNEUROSCI.4317-05.2006 (2006).","journal-title":"J. Neurosci."},{"key":"86191_CR25","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1089\/jir.2014.0012","volume":"34","author":"EN Benveniste","year":"2014","unstructured":"Benveniste, E. N., Liu, Y., McFarland, B. C. & Qin, H. Involvement of the janus kinase\/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis. J. Interferon Cytokine Res. 34, 577\u2013588. https:\/\/doi.org\/10.1089\/jir.2014.0012 (2014).","journal-title":"J. Interferon Cytokine Res."},{"key":"86191_CR26","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.biochi.2015.09.022","volume":"122","author":"E Dall","year":"2016","unstructured":"Dall, E. & Brandstetter, H. Structure and function of legumain in health and disease. Biochimie 122, 126\u2013150. https:\/\/doi.org\/10.1016\/j.biochi.2015.09.022 (2016).","journal-title":"Biochimie"},{"key":"86191_CR27","doi-asserted-by":"publisher","first-page":"10200","DOI":"10.1073\/pnas.0504754102","volume":"102","author":"C Zhao","year":"2005","unstructured":"Zhao, C., Denison, C., Huibregtse, J. M., Gygi, S. & Krug, R. M. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc. Natl. Acad. Sci. U.S.A. 102, 10200\u201310205. https:\/\/doi.org\/10.1073\/pnas.0504754102 (2005).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"86191_CR28","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1111\/cen3.12208","volume":"6","author":"J-I Satoh","year":"2015","unstructured":"Satoh, J.-I., Asahina, N., Kitano, S. & Kino, Y. Legumain is expressed on macrophages in active demyelinating lesions of multiple sclerosis. Clin. Exp. Neuroimmunol. 6, 304\u2013305. https:\/\/doi.org\/10.1111\/cen3.12208 (2015).","journal-title":"Clin. Exp. Neuroimmunol."},{"key":"86191_CR29","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/2051-5960-2-53","volume":"2","author":"G Ingram","year":"2014","unstructured":"Ingram, G. et al. Complement activation in multiple sclerosis plaques: An immunohistochemical analysis. Acta Neuropathol. Commun. 2, 53. https:\/\/doi.org\/10.1186\/2051-5960-2-53 (2014).","journal-title":"Acta Neuropathol. Commun."},{"key":"86191_CR30","doi-asserted-by":"publisher","first-page":"2048","DOI":"10.1021\/pr201244t","volume":"11","author":"T Rosenling","year":"2012","unstructured":"Rosenling, T. et al. Profiling and identification of cerebrospinal fluid proteins in a rat EAE model of multiple sclerosis. J. Proteome Res. 11, 2048\u20132060. https:\/\/doi.org\/10.1021\/pr201244t (2012).","journal-title":"J. Proteome Res."},{"key":"86191_CR31","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1177\/1352458508100047","volume":"15","author":"KN Rithidech","year":"2009","unstructured":"Rithidech, K. N. et al. Protein expression profiles in pediatric multiple sclerosis: Potential biomarkers. Mult. Scler. 15, 455\u2013464. https:\/\/doi.org\/10.1177\/1352458508100047 (2009).","journal-title":"Mult. Scler."},{"key":"86191_CR32","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.it.2013.04.006","volume":"34","author":"SB Simmons","year":"2013","unstructured":"Simmons, S. B., Pierson, E. R., Lee, S. Y. & Goverman, J. M. Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 34, 410\u2013422. https:\/\/doi.org\/10.1016\/j.it.2013.04.006 (2013).","journal-title":"Trends Immunol."},{"key":"86191_CR33","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jneuroim.2008.09.009","volume":"205","author":"T Zeis","year":"2008","unstructured":"Zeis, T., Kinter, J., Herrero-Herranz, E., Weissert, R. & Schaeren-Wiemers, N. Gene expression analysis of normal appearing brain tissue in an animal model for multiple sclerosis revealed grey matter alterations, but only minor white matter changes. J. Neuroimmunol. 205, 10\u201319. https:\/\/doi.org\/10.1016\/j.jneuroim.2008.09.009 (2008).","journal-title":"J. Neuroimmunol."},{"key":"86191_CR34","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.neuroscience.2011.04.041","volume":"185","author":"A Castegna","year":"2011","unstructured":"Castegna, A. et al. Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience 185, 97\u2013105. https:\/\/doi.org\/10.1016\/j.neuroscience.2011.04.041 (2011).","journal-title":"Neuroscience"},{"key":"86191_CR35","doi-asserted-by":"publisher","first-page":"2010","DOI":"10.1016\/j.bbadis.2010.02.006","volume":"485\u2013496","author":"YJ Jeon","year":"1802","unstructured":"Jeon, Y. J., Yoo, H. M. & Chung, C. H. ISG15 and immune diseases. Biochim. Biophys. Acta 485\u2013496, 2010. https:\/\/doi.org\/10.1016\/j.bbadis.2010.02.006 (1802).","journal-title":"Biochim. Biophys. Acta"},{"key":"86191_CR36","doi-asserted-by":"publisher","first-page":"2421","DOI":"10.1111\/j.1582-4934.2010.01229.x","volume":"15","author":"D Haves-Zburof","year":"2011","unstructured":"Haves-Zburof, D. et al. Cathepsins and their endogenous inhibitors cystatins: Expression and modulation in multiple sclerosis. J. Cell Mol. Med. 15, 2421\u20132429. https:\/\/doi.org\/10.1111\/j.1582-4934.2010.01229.x (2011).","journal-title":"J. Cell Mol. Med."},{"key":"86191_CR37","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/ni754","volume":"3","author":"B Manoury","year":"2002","unstructured":"Manoury, B. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat. Immunol. 3, 169\u2013174. https:\/\/doi.org\/10.1038\/ni754 (2002).","journal-title":"Nat. Immunol."},{"key":"86191_CR38","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1515\/hsz-2014-0172","volume":"396","author":"R Solberg","year":"2015","unstructured":"Solberg, R. et al. Legumain expression, activity and secretion are increased during monocyte-to-macrophage differentiation and inhibited by atorvastatin. Biol. Chem. 396, 71\u201380. https:\/\/doi.org\/10.1515\/hsz-2014-0172 (2015).","journal-title":"Biol. Chem."},{"key":"86191_CR39","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1038\/nm.3700","volume":"20","author":"Z Zhang","year":"2014","unstructured":"Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer\u2019s disease. Nat. Med. 20, 1254\u20131262. https:\/\/doi.org\/10.1038\/nm.3700 (2014).","journal-title":"Nat. Med."},{"key":"86191_CR40","doi-asserted-by":"publisher","first-page":"17495","DOI":"10.1074\/jbc.M112.446070","volume":"288","author":"G Basurto-Islas","year":"2013","unstructured":"Basurto-Islas, G., Grundke-Iqbal, I., Tung, Y. C., Liu, F. & Iqbal, K. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. J. Biol. Chem. 288, 17495\u201317507. https:\/\/doi.org\/10.1074\/jbc.M112.446070 (2013).","journal-title":"J. Biol. Chem."},{"key":"86191_CR41","doi-asserted-by":"publisher","first-page":"e52980","DOI":"10.1371\/journal.pone.0052980","volume":"8","author":"MH Haugen","year":"2013","unstructured":"Haugen, M. H. et al. Nuclear legumain activity in colorectal cancer. PLoS ONE 8, e52980. https:\/\/doi.org\/10.1371\/journal.pone.0052980 (2013).","journal-title":"PLoS ONE"},{"key":"86191_CR42","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ejca.2014.10.020","volume":"51","author":"MH Haugen","year":"2015","unstructured":"Haugen, M. H. et al. High expression of the cysteine proteinase legumain in colorectal cancer\u2014Implications for therapeutic targeting. Eur. J. Cancer 51, 9\u201317. https:\/\/doi.org\/10.1016\/j.ejca.2014.10.020 (2015).","journal-title":"Eur. J. Cancer"},{"key":"86191_CR43","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nn.3588","volume":"17","author":"JL Huynh","year":"2014","unstructured":"Huynh, J. L. et al. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat. Neurosci. 17, 121\u2013130. https:\/\/doi.org\/10.1038\/nn.3588 (2014).","journal-title":"Nat. Neurosci."},{"key":"86191_CR44","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1016\/j.bbapap.2014.12.013","volume":"746\u2013756","author":"AC Kroksveen","year":"1854","unstructured":"Kroksveen, A. C. et al. Cerebrospinal fluid proteomics in multiple sclerosis. Biochim. Biophys. Acta 746\u2013756, 2015. https:\/\/doi.org\/10.1016\/j.bbapap.2014.12.013 (1854).","journal-title":"Biochim. Biophys. Acta"},{"key":"86191_CR45","doi-asserted-by":"publisher","unstructured":"Kroksveen, A. C. et al. Cerebrospinal fluid proteome comparison between multiple sclerosis patients and controls. Acta Neurol. Scand. Suppl. 90\u201396, https:\/\/doi.org\/10.1111\/ane.12029 (2012).","DOI":"10.1111\/ane.12029"},{"key":"86191_CR46","doi-asserted-by":"publisher","first-page":"12138","DOI":"10.1073\/pnas.0604911103","volume":"103","author":"S Herculano-Houzel","year":"2006","unstructured":"Herculano-Houzel, S., Mota, B. & Lent, R. Cellular scaling rules for rodent brains. Proc. Natl. Acad. Sci. U.S.A. 103, 12138\u201312143. https:\/\/doi.org\/10.1073\/pnas.0604911103 (2006).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"86191_CR47","doi-asserted-by":"publisher","first-page":"285245","DOI":"10.1155\/2014\/285245","volume":"2014","author":"SS Duffy","year":"2014","unstructured":"Duffy, S. S., Lees, J. G. & Moalem-Taylor, G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult. Scler. Int. 2014, 285245. https:\/\/doi.org\/10.1155\/2014\/285245 (2014).","journal-title":"Mult. Scler. Int."},{"key":"86191_CR48","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.brainres.2010.10.003","volume":"1367","author":"T Wang","year":"2011","unstructured":"Wang, T. et al. Human Ermin (hErmin), a new oligodendrocyte-specific cytoskeletal protein related to epileptic seizure. Brain Res. 1367, 77\u201384. https:\/\/doi.org\/10.1016\/j.brainres.2010.10.003 (2011).","journal-title":"Brain Res."},{"key":"86191_CR49","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/nn.3599","volume":"17","author":"O Butovsky","year":"2014","unstructured":"Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131\u2013143. https:\/\/doi.org\/10.1038\/nn.3599 (2014).","journal-title":"Nat. Neurosci."},{"key":"86191_CR50","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/j.nbd.2013.10.023","volume":"62","author":"HC Hoyos","year":"2014","unstructured":"Hoyos, H. C. et al. Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination. Neurobiol. Dis. 62, 441\u2013455. https:\/\/doi.org\/10.1016\/j.nbd.2013.10.023 (2014).","journal-title":"Neurobiol. Dis."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86191-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86191-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86191-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T05:57:13Z","timestamp":1670047033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86191-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,30]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["86191"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-86191-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,30]]},"assertion":[{"value":"30 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7174"}}