{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:18:44Z","timestamp":1787818724629,"version":"build-2784847793"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":225,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United Kingdom Multiple Sclerosis Society","award":["HMR04500"],"award-info":[{"award-number":["HMR04500"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cortical neurodegeneration and glial activation are major drivers of disability progression in multiple sclerosis, but the molecular mechanisms underlying these processes remain poorly defined. Members of the NR4A nuclear receptor family are stress-responsive transcription factors that regulate neuronal survival, inflammatory signalling and cellular adaptation to metabolic and oxidative stress. In particular, neuron-derived orphan receptor 1 (NR4A3) has been implicated in neuroprotective and stress-adaptive responses in other neurological conditions, but its role in multiple sclerosis has not been investigated. Given its dual involvement in neuronal stress regulation and inflammatory modulation, neuron-derived orphan receptor 1 represents a plausible molecular link between chronic neuroinflammation, biological ageing and cortical neurodegeneration in multiple sclerosis. Here, we examined neuron-derived orphan receptor 1 expression in the motor cortex of post-mortem multiple sclerosis (n = 50) and control (n = 10) cases across lesional and non-lesional cortical layers of the motor cortex. Neuron-derived orphan receptor 1 was expressed by various cell types but predominantly localized to the neuronal cytoplasm and was reduced in multiple sclerosis non-lesional grey matter compared with controls, in particular in the functionally relevant layer V. In layer V, neuron-derived orphan receptor 1 loss was linked to exacerbated astrocytic (GFAP+) and microglial\/macrophage (CD68+) expression, and higher levels of senescence markers (p19^INK4d, p21^CIP1), suggesting that loss of neuron-derived orphan receptor 1 relates to neuroinflammation and biological ageing processes. In contrast, in layer III, neuron-derived orphan receptor 1 expression was positively associated with neuronal density (NeuN) and Nurr1 expression, a transcription factor from the same NR4A family with established neuroprotective functions. Together, our findings identify neuron-derived orphan receptor 1 as a previously unrecognized, layer-specific regulator of cortical pathology in multiple sclerosis. Loss of neuron-derived orphan receptor 1 in deep-layer projection neurons aligns with inflammatory amplification and ageing-associated stress responses, whereas its preservation in upper layers may support neuronal integrity and neuroprotective signalling. These data position neuron-derived orphan receptor 1 as a candidate molecular node linking neuroinflammation, senescence and cortical neurodegeneration in progressive multiple sclerosis, and support that strategies aimed at preserving or restoring neuron-derived orphan receptor 1 activity may support neuron resilience and mitigate cortical disease progression in this incurable disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag315","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:12:02Z","timestamp":1786705922000},"source":"Crossref","is-referenced-by-count":0,"title":["NOR1 loss relates to inflammation and biological ageing in multiple sclerosis motor cortex"],"prefix":"10.1093","volume":"8","author":[{"given":"Buse","family":"Unlu Kobya","sequence":"first","affiliation":[{"name":"University of Oxford Nuffield Department of Clinical Neurosciences, , Oxford, Oxfordshire ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee","family":"Avery","sequence":"additional","affiliation":[{"name":"University of Oxford Nuffield Department of Clinical Neurosciences, , Oxford, Oxfordshire ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"DeLuca","sequence":"additional","affiliation":[{"name":"University of Oxford Nuffield Department of Clinical Neurosciences, , Oxford, Oxfordshire ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8918-9943","authenticated-orcid":false,"given":"Jonathan","family":"Pansieri","sequence":"additional","affiliation":[{"name":"University of Oxford Nuffield Department of Clinical Neurosciences, , Oxford, Oxfordshire ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026082703465921800_fcag315-B1","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1056\/NEJMoa1100648","article-title":"Inflammatory cortical demyelination in early multiple sclerosis","volume":"365","author":"Lucchinetti","year":"2011","journal-title":"N Engl J Med"},{"issue":"11","key":"2026082703465921800_fcag315-B2","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1093\/brain\/awh641","article-title":"Cortical demyelination and diffuse white matter injury in multiple sclerosis","volume":"128","author":"Kutzelnigg","year":"2005","journal-title":"Brain"},{"key":"2026082703465921800_fcag315-B3","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.3389\/fimmu.2018.03116","article-title":"Pathogenic mechanisms associated with different clinical courses of multiple sclerosis","volume":"9","author":"Lassmann","year":"2019","journal-title":"Front Immunol"},{"key":"2026082703465921800_fcag315-B4","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1586\/ern.10.155","article-title":"Cortical pathology and cognitive impairment in multiple sclerosis","volume":"11","author":"Calabrese","year":"2011","journal-title":"Expert Rev Neurother"},{"issue":"Pt 4","key":"2026082703465921800_fcag315-B5","first-page":"1089","article-title":"Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology","volume":"130","author":"Magliozzi","year":"2007","journal-title":"Brain"},{"issue":"3","key":"2026082703465921800_fcag315-B6","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/brain\/awv398","article-title":"The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain","volume":"139","author":"Haider","year":"2016","journal-title":"Brain"},{"key":"2026082703465921800_fcag315-B7","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1600-0404.2006.00615.x","article-title":"Grey matter pathology in multiple sclerosis","volume":"113","author":"B\u00f6","year":"2006","journal-title":"Acta Neurol Scand"},{"key":"2026082703465921800_fcag315-B8","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/ana.27195","article-title":"Accelerated cellular senescence in progressive multiple sclerosis: A histopathological study","volume":"97","author":"Papadopoulos","year":"2025","journal-title":"Ann Neurol"},{"issue":"6","key":"2026082703465921800_fcag315-B9","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1093\/brain\/awt110","article-title":"Disease-specific molecular events in cortical multiple sclerosis lesions","volume":"136","author":"Fischer","year":"2013","journal-title":"Brain"},{"issue":"5","key":"2026082703465921800_fcag315-B10","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1093\/brain\/awp070","article-title":"The relation between inflammation and neurodegeneration in multiple sclerosis brains","volume":"132","author":"Frischer","year":"2009","journal-title":"Brain"},{"key":"2026082703465921800_fcag315-B11","first-page":"e002","article-title":"The NR4A subgroup: Immediate early response genes with pleiotropic physiological roles","volume":"4","author":"Maxwell","year":"2018","journal-title":"Nucl Recept Signal"},{"issue":"27","key":"2026082703465921800_fcag315-B12","doi-asserted-by":"crossref","first-page":"12317","DOI":"10.1073\/pnas.1007088107","article-title":"NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection","volume":"107","author":"Volakakis","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1\u20132","key":"2026082703465921800_fcag315-B13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.brainresbull.2011.02.001","article-title":"The role of NR4A transcription factors in memory formation","volume":"85","author":"Hawk","year":"2011","journal-title":"Brain Res Bull"},{"issue":"2","key":"2026082703465921800_fcag315-B14","doi-asserted-by":"crossref","first-page":"fcad072","DOI":"10.1093\/braincomms\/fcad072","article-title":"A potential protective role of the nuclear receptor-related factor 1 (Nurr1) in multiple sclerosis motor cortex: A neuropathological study","volume":"5","author":"Pansieri","year":"2023","journal-title":"Brain Commun"},{"key":"2026082703465921800_fcag315-B15","doi-asserted-by":"crossref","first-page":"981490","DOI":"10.3389\/fphar.2022.981490","article-title":"Comprehensive insights into the function and molecular and pharmacological regulation of neuron-derived orphan receptor 1, an orphan receptor","volume":"13","author":"Hong","year":"2022","journal-title":"Front Pharmacol"},{"issue":"1","key":"2026082703465921800_fcag315-B16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13578-024-01273-x","article-title":"SUMOylation of nuclear receptor Nor1\/NR4A3 coordinates microtubule cytoskeletal dynamics and stability in neuronal cells","volume":"14","author":"Gagnon","year":"2024","journal-title":"Cell Biosci"},{"issue":"20","key":"2026082703465921800_fcag315-B17","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.3390\/ijms232012455","article-title":"Nr1d1 mediated cell senescence in mouse heart-derived Sca-1+CD31\u2212 cells","volume":"23","author":"Pu","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"6703","key":"2026082703465921800_fcag315-B18","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1126\/science.adi3450","article-title":"Neuronal senescence may drive brain aging","volume":"384","author":"Herdy","year":"2024","journal-title":"Science"},{"key":"2026082703465921800_fcag315-B19","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s42003-022-03032-5","article-title":"Lamina-specific immunohistochemical signatures in the olfactory bulb of healthy, Alzheimer\u2019s and Parkinson\u2019s disease patients","volume":"5","author":"Murray","year":"2022","journal-title":"Commun Biol"},{"issue":"1","key":"2026082703465921800_fcag315-B20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1471-2377-12-11","article-title":"Meningeal and cortical grey matter pathology in multiple sclerosis","volume":"12","author":"Gh Popescu","year":"2012","journal-title":"BMC Neurol"},{"issue":"6","key":"2026082703465921800_fcag315-B21","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/0301-0082(92)90015-7","article-title":"The pyramidal neuron of the cerebral cortex: Morphological and chemical characteristics of the synaptic inputs","volume":"39","author":"DeFelipe","year":"1992","journal-title":"Prog Neurobiol"},{"key":"2026082703465921800_fcag315-B22","doi-asserted-by":"crossref","first-page":"780026","DOI":"10.3389\/fcomp.2021.780026","article-title":"An open-source whole slide image registration workflow at cellular precision using Fiji, QuPath and elastix","volume":"3","author":"Chiaruttini","year":"2022","journal-title":"Front Comput Sci"},{"key":"2026082703465921800_fcag315-B23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jneuroim.2017.04.007","article-title":"Staining of HLA-DR, Iba1 and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology","volume":"309","author":"Hendrickx","year":"2017","journal-title":"J Neuroimmunol"},{"issue":"2","key":"2026082703465921800_fcag315-B24","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/ana.24997","article-title":"Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex","volume":"82","author":"Yates","year":"2017","journal-title":"Ann Neurol"},{"key":"2026082703465921800_fcag315-B25","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1002\/ana.27231","article-title":"Neuropathological evidence of reduced amyloid beta and neurofibrillary tangles in multiple sclerosis cortex","volume":"97","author":"Pansieri","year":"2025","journal-title":"Ann Neurol"},{"issue":"2","key":"2026082703465921800_fcag315-B26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/nan.12559","article-title":"Expression of p16 and p21 in the frontal association cortex of ALS\/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease","volume":"46","author":"Vazquez-Villase\u00f1or","year":"2020","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"2","key":"2026082703465921800_fcag315-B27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.mehy.2014.12.003","article-title":"The NR4A nuclear receptors as potential targets for anti-aging interventions","volume":"84","author":"Paillasse","year":"2015","journal-title":"Med Hypotheses"},{"key":"2026082703465921800_fcag315-B28","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.nlm.2013.06.020","article-title":"The NR4A orphan nuclear receptors mediate transcription-dependent hippocampal synaptic plasticity","volume":"105","author":"Bridi","year":"2013","journal-title":"Neurobiol Learn Mem"},{"issue":"10","key":"2026082703465921800_fcag315-B29","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/S1474-4422(18)30245-X","article-title":"Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: A retrospective study","volume":"17","author":"Trapp","year":"2018","journal-title":"Lancet Neurol"},{"issue":"1","key":"2026082703465921800_fcag315-B30","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/brain\/awv353","article-title":"Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis","volume":"139","author":"J\u00fcrgens","year":"2016","journal-title":"Brain"},{"issue":"8925","key":"2026082703465921800_fcag315-B31","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S0140-6736(94)92338-8","article-title":"Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer\u2019s disease","volume":"344","author":"West","year":"1994","journal-title":"The Lancet"},{"key":"2026082703465921800_fcag315-B32","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0079-6123(02)36039-4","article-title":"Chapter 37 selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer\u2019s disease","volume":"136","author":"Morrison","year":"2002","journal-title":"Prog Brain Res"},{"issue":"2","key":"2026082703465921800_fcag315-B33","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrn.2016.178","article-title":"Selective neuronal vulnerability in Parkinson disease","volume":"18","author":"Surmeier","year":"2017","journal-title":"Nat Rev Neurosci"},{"issue":"1","key":"2026082703465921800_fcag315-B34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nn1618","article-title":"Molecular taxonomy of major neuronal classes in the adult mouse forebrain","volume":"9","author":"Sugino","year":"2006","journal-title":"Nat Neurosci"},{"issue":"11","key":"2026082703465921800_fcag315-B35","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.3390\/cells8111373","article-title":"Function of Nr4a orphan nuclear receptors in proliferation, apoptosis and fuel utilization across tissues","volume":"8","author":"Herring","year":"2019","journal-title":"Cells"},{"key":"2026082703465921800_fcag315-B36","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1161\/ATVBAHA.109.191163","article-title":"NR4A orphan nuclear receptors","volume":"30","author":"Zhao","year":"2010","journal-title":"Arterioscler Thrombo Vasc Biol"},{"issue":"1","key":"2026082703465921800_fcag315-B37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s00401-025-02923-1","article-title":"A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: A link to smoldering progression","volume":"150","author":"Mu\u00f1oz Gonz\u00e1lez","year":"2025","journal-title":"Acta Neuropathol"},{"issue":"1","key":"2026082703465921800_fcag315-B38","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1007\/s00018-025-05755-0","article-title":"NR4A2 attenuates early brain injury after intracerebral hemorrhage by promoting M2 microglial polarization via TLR4\/TRAF6\/NF-\u03baB pathway inhibition","volume":"82","author":"Hu","year":"2025","journal-title":"Cell Mol Life Sci"},{"issue":"4","key":"2026082703465921800_fcag315-B39","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1210\/me.2005-0331","article-title":"Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77","volume":"20","author":"Pei","year":"2006","journal-title":"Mol Endocrinol"},{"issue":"1","key":"2026082703465921800_fcag315-B40","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cell.2009.01.038","article-title":"A Nurr1\/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death","volume":"137","author":"Saijo","year":"2009","journal-title":"Cell"},{"issue":"10","key":"2026082703465921800_fcag315-B41","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.4049\/jimmunol.1600638","article-title":"The nuclear receptor Nr4a1 acts as a microglia rheostat and serves as a therapeutic target in autoimmune-driven central nervous system inflammation","volume":"198","author":"Rothe","year":"2017","journal-title":"J Immunol"},{"issue":"9","key":"2026082703465921800_fcag315-B42","doi-asserted-by":"crossref","first-page":"e108791","DOI":"10.1371\/journal.pone.0108791","article-title":"Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in mice","volume":"9","author":"Montarolo","year":"2014","journal-title":"PLoS One"},{"issue":"6","key":"2026082703465921800_fcag315-B43","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/j.1600-0854.2010.01063.x","article-title":"Nucleolar disruption ensures nuclear accumulation of p21 upon DNA damage","volume":"11","author":"Abella","year":"2010","journal-title":"Traffic"},{"issue":"9","key":"2026082703465921800_fcag315-B44","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.3390\/cancers11091220","article-title":"The multifaceted p21 (Cip1\/Waf1\/CDKN1A) in cell differentiation, migration and cancer therapy","volume":"11","author":"Kreis","year":"2019","journal-title":"Cancers (Basel)"},{"issue":"1","key":"2026082703465921800_fcag315-B45","doi-asserted-by":"crossref","first-page":"e16301","DOI":"10.1111\/jnc.16301","article-title":"Cellular senescence in glial cells: Implications for multiple sclerosis","volume":"169","author":"Maupin","year":"2025","journal-title":"J Neurochem"},{"issue":"12","key":"2026082703465921800_fcag315-B46","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/s43587-021-00142-3","article-title":"Profiling senescent cells in human brains reveals neurons with CDKN2D\/p19 and tau neuropathology","volume":"1","author":"Dehkordi","year":"2021","journal-title":"Nat Aging"},{"key":"2026082703465921800_fcag315-B47","doi-asserted-by":"crossref","first-page":"646924","DOI":"10.3389\/fnagi.2021.646924","article-title":"Cellular senescence in brain aging","volume":"13","author":"Sikora","year":"2021","journal-title":"Front Aging Neurosci"},{"issue":"4","key":"2026082703465921800_fcag315-B48","doi-asserted-by":"crossref","first-page":"e3002559","DOI":"10.1371\/journal.pbio.3002559","article-title":"Neuronal cell cycle reentry events in the aging brain are more prevalent in neurodegeneration and lead to cellular senescence","volume":"22","author":"Wu","year":"2024","journal-title":"PLoS Biol"},{"issue":"1","key":"2026082703465921800_fcag315-B49","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0304-3940(87)90698-7","article-title":"Ubiquitin-protein conjugates in Alzheimer\u2019s lesions","volume":"79","author":"Cole","year":"1987","journal-title":"Neurosci Lett"},{"issue":"2","key":"2026082703465921800_fcag315-B50","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/j.1582-4934.2008.00276.x","article-title":"The ubiquitin-proteasome system in Alzheimer\u2019s disease","volume":"12","author":"Oddo","year":"2008","journal-title":"J Cell Mol Med"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcag315\/70650246\/fcag315.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/4\/fcag315\/70650246\/fcag315.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/4\/fcag315\/70650246\/fcag315.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T07:47:08Z","timestamp":1787816828000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcag315\/8761589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":50,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcag315","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"fcag315"}}