{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:48:55Z","timestamp":1792795735527,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T00:00:00Z","timestamp":1728000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["23K14675"],"award-info":[{"award-number":["23K14675"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["J53D23000970006"],"award-info":[{"award-number":["J53D23000970006"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union Next Generation EU","award":["23K14675"],"award-info":[{"award-number":["23K14675"]}]},{"name":"European Union Next Generation EU","award":["J53D23000970006"],"award-info":[{"award-number":["J53D23000970006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to explore the intricate relationship between mitochondrial dysfunction, infection, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of the Epstein\u2013Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2\u2212\/\u2212 and C57BL\/6J wild-type mice immunized with EBNA1386\u2013405 or with active experimental autoimmune encephalomyelitis (EAE) induction by the myelin oligodendrocyte glycoprotein (MOG)35\u201355 peptide. The PARK2\u2212\/\u2212 mice developed more severe EAE than the wild-type mice. Following immunization with EBNA1386\u2013405, only PARK2\u2212\/\u2212 exhibited symptoms resembling EAE. During the acute phase, PARK2\u2212\/\u2212 mice immunized with either MOG35\u201355 or EBNA1386\u2013405 exhibited a similar infiltration of the T cells and macrophages in the spinal cord and decreased glial fibrillary acidic protein (GFAP) expression in the brain. However, the EBNA1386\u2013405 -immunized PARK2\u2212\/\u2212 mice showed significantly increased frequencies of CD8a+ T cells and CD11c+ B cells, and distinct cytokine profiles in the periphery compared to the wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies.<\/jats:p>","DOI":"10.3390\/ijms251910697","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T07:49:42Z","timestamp":1728028182000},"page":"10697","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impact of Epstein\u2013Barr Virus Nuclear Antigen 1 on Neuroinflammation in PARK2 Knockout Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-9467","authenticated-orcid":false,"given":"Davide","family":"Cossu","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University, Tokyo 1138431, Japan"},{"name":"Biomedical Research Core Facilities, Juntendo University, Tokyo 1138431, Japan"},{"name":"Department of Biomedical Sciences, Sassari University, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5462-6725","authenticated-orcid":false,"given":"Yuji","family":"Tomizawa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Juntendo University, Tokyo 1138431, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Noda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Juntendo University, Tokyo 1138431, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4765-1866","authenticated-orcid":false,"given":"Eiichi","family":"Momotani","sequence":"additional","affiliation":[{"name":"Comparative Medical Research Institute, Tsukuba 305-0856, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamami","family":"Sakanishi","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, Juntendo University, Tokyo 1138431, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Neurology, Juntendo University, Tokyo 1138431, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0950-1093","authenticated-orcid":false,"given":"Kazumasa","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Neurology, Juntendo University, Tokyo 1138431, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0566-2049","authenticated-orcid":false,"given":"Leonardo Antonio","family":"Sechi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Sassari University, 07100 Sassari, Italy"},{"name":"Complex Structure of Microbiology and Virology, University Hospital, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2034-2556","authenticated-orcid":false,"given":"Nobutaka","family":"Hattori","sequence":"additional","affiliation":[{"name":"Department of Neurology, Juntendo University, Tokyo 1138431, Japan"},{"name":"Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama 3510918, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3389\/fimmu.2015.00520","article-title":"Infection as an Environmental Trigger of Multiple Sclerosis Disease Exacerbation","volume":"6","author":"Steelman","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41579-022-00770-5","article-title":"Epstein-Barr virus and multiple sclerosis","volume":"21","author":"Soldan","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","first-page":"160","article-title":"Epstein-Barr virus as a leading cause of multiple sclerosis: Mechanisms and implications","volume":"19","author":"Bjornevik","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/s41590-022-01156-8","article-title":"Molecular mimicry in MS","volume":"23","author":"Dempsey","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jcv.2018.03.001","article-title":"Primary Epstein-Barr virus infection","volume":"102","author":"Dunmire","year":"2018","journal-title":"J. Clin. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Barcelos, I.P., Troxell, R.M., and Graves, J.S. (2019). Mitochondrial Dysfunction and Multiple Sclerosis. Biology, 8.","DOI":"10.3390\/biology8020037"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12974-024-03016-8","article-title":"Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis","volume":"21","author":"Wang","year":"2024","journal-title":"J. Neuroinflamm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.tcb.2020.01.006","article-title":"Mitochondrial Functions in Infection and Immunity","volume":"30","author":"Tiku","year":"2020","journal-title":"Trends Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1359600","DOI":"10.3389\/fimmu.2024.1359600","article-title":"ROS signaling in innate immunity via oxidative protein modifications","volume":"15","author":"Manoharan","year":"2024","journal-title":"Front. Immunol."},{"key":"ref_10","first-page":"10","article-title":"Mitophagy and Innate Immunity in Infection","volume":"43","author":"Cho","year":"2020","journal-title":"Mol. Cells"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.biocel.2014.05.012","article-title":"Regulation by mitophagy","volume":"53","author":"Hattori","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"577694","DOI":"10.1016\/j.jneuroim.2021.577694","article-title":"PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE)","volume":"359","author":"Cossu","year":"2021","journal-title":"J. Neuroimmunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1036680","DOI":"10.3389\/fimmu.2022.1036680","article-title":"Age related immune modulation of experimental autoimmune encephalomyelitis in PINK1 knockout mice","volume":"13","author":"Cossu","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Noda, S., Sato, S., Fukuda, T., Tada, N., Uchiyama, Y., Tanaka, K., and Hattori, N. (2020). Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice. Neurobiol. Dis., 136.","DOI":"10.1016\/j.nbd.2019.104717"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41586-019-1405-y","article-title":"Intestinal infection triggers Parkinson\u2019s disease-like symptoms in Pink1(-\/-) mice","volume":"571","author":"Matheoud","year":"2019","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41586-022-04432-7","article-title":"Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM","volume":"603","author":"Lanz","year":"2022","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.cell.2016.05.039","article-title":"Parkinson\u2019s Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation","volume":"166","author":"Matheoud","year":"2016","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Veroni, C., and Aloisi, F. (2021). The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.665718"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mouat, I.C., Shanina, I., and Horwitz, M.S. (2022). Age-associated B cells are long-lasting effectors that impede latent gammaHV68 reactivation. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-25543-1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3389\/fimmu.2020.00032","article-title":"CD11c(+) B Cells Are Mainly Memory Cells, Precursors of Antibody Secreting Cells in Healthy Donors","volume":"11","author":"Golinski","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"eade6844","DOI":"10.1126\/sciadv.ade6844","article-title":"Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS","volume":"8","author":"Mouat","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1007\/s12026-022-09291-y","article-title":"Involvement of age-associated B cells in EBV-triggered autoimmunity","volume":"70","author":"Sachinidis","year":"2022","journal-title":"Immunol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s12264-018-0228-4","article-title":"GFAP-Positive Progenitor Cell Production is Concentrated in Specific Encephalic Regions in Young Adult Mice","volume":"34","author":"Guo","year":"2018","journal-title":"Neurosci. Bull."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1383728","DOI":"10.3389\/fnins.2024.1383728","article-title":"A coming-of-age story: Adult neurogenesis or adolescent neurogenesis in rodents?","volume":"18","author":"Arellano","year":"2024","journal-title":"Front. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1001\/jamaneurol.2022.4655","article-title":"Association of Early Progression Independent of Relapse Activity with Long-term Disability After a First Demyelinating Event in Multiple Sclerosis","volume":"80","author":"Tur","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Srivastava, S. (2017). The Mitochondrial Basis of Aging and Age-Related Disorders. Genes, 8.","DOI":"10.3390\/genes8120398"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"264","DOI":"10.21037\/atm-22-2401","article-title":"Mitochondrial dynamics in neurological diseases: A narrative review","volume":"11","author":"Shen","year":"2023","journal-title":"Ann. Transl. Med."},{"key":"ref_28","first-page":"88","article-title":"Parkinsonism associated with multiple sclerosis: A report of eight new cases and a review on the literature","volume":"13","author":"Etemadifar","year":"2014","journal-title":"Iran. J. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1177\/1352458512445942","article-title":"Primary progressive multiple sclerosis developing in the context of young onset Parkinson\u2019s disease","volume":"19","author":"Sadnicka","year":"2013","journal-title":"Mult. Scler."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"681386","DOI":"10.3389\/fimmu.2021.681386","article-title":"Potential of PINK1 and PARKIN Proteins as Biomarkers for Active Multiple Sclerosis: A Japanese Cohort Study","volume":"12","author":"Cossu","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106197","DOI":"10.1016\/j.clineuro.2020.106197","article-title":"Evaluation of the Diagnostic and Predictive Value of Serum Levels of ANT1, ATG5, and Parkin in Multiple Sclerosis","volume":"197","author":"Nourazarian","year":"2020","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41392-020-0151-9","article-title":"Drp1-dependent remodeling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.irn.2022.07.005","article-title":"Parkinsonism associated with viral infection","volume":"165","author":"Ivan","year":"2022","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tiwari, D., Mittal, N., and Jha, H.C. (2022). Unraveling the links between neurodegeneration and Epstein-Barr virus-mediated cell cycle dysregulation. Curr. Res. Neurobiol., 3.","DOI":"10.1016\/j.crneur.2022.100046"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1175874","DOI":"10.3389\/fimmu.2023.1175874","article-title":"Potential biological contributers to the sex difference in multiple sclerosis progression","volume":"14","author":"Dunn","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1353865","DOI":"10.3389\/fimmu.2024.1353865","article-title":"Complete Freund\u2019s adjuvant as a confounding factor in multiple sclerosis research","volume":"15","author":"Lazarevic","year":"2024","journal-title":"Front. Immunol."},{"key":"ref_37","first-page":"e65422","article-title":"Adjuvant Activity of Mycobacterium paratuberculosis in Enhancing the Immunogenicity of Autoantigens During Experimental Autoimmune Encephalomyelitis","volume":"195","author":"Cossu","year":"2023","journal-title":"J. Vis. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1002\/jnr.21032","article-title":"Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography","volume":"84","author":"Sato","year":"2006","journal-title":"J. Neurosci. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10697\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:10:38Z","timestamp":1760112638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,4]]},"references-count":38,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910697"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910697","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,4]]}}}