{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:20:29Z","timestamp":1790630429339,"version":"4.1.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"8115","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2026,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease\n                    <jats:sup>1<\/jats:sup>\n                    , but the underlying mechanisms for cell-type-specific neuronal losses remain poorly understood. Previous studies have shown that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) and that cortical layer 2\u00a0and layer\u00a03\u00a0(L2\/3) excitatory neurons (L2\/3ENs) that express CUT-like homeobox 2 (\n                    <jats:italic>CUX2<\/jats:italic>\n                    ) are selectively vulnerable to degeneration\n                    <jats:sup>2<\/jats:sup>\n                    . Here we report that L2\/3ENs within MS cortical lesions have an elevated DNA damage burden. DNA damage and selective loss of L2\/3ENs were recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability. Functions of\n                    <jats:italic>Cux2<\/jats:italic>\n                    and activating transcription factor 4 (\n                    <jats:italic>Atf4<\/jats:italic>\n                    ) were essential for resilience of L2\/3ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double-strand break repair. Interferon-\u03b3, a cytokine implicated in MS pathogenesis\n                    <jats:sup>3,4<\/jats:sup>\n                    , was sufficient to elevate\u00a0levels of reactive oxygen species, leading to DNA\u00a0damage-mediated neuronal death in vitro, and caused selective depletion of L2\/3 neurons in mice. These findings indicate that DNA damage burden and inadequate repair in CUX2\n                    <jats:sup>+<\/jats:sup>\n                    L2\/3ENs contributes to selective vulnerability in neuroinflammatory injury.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10310-3","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T15:02:53Z","timestamp":1775055773000},"page":"809-818","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["DNA damage burden causes selective CUX2 neuron loss in neuroinflammation"],"prefix":"10.1038","volume":"653","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6683-4356","authenticated-orcid":false,"given":"Laura","family":"Morcom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashika","family":"Awasthi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1222-2627","authenticated-orcid":false,"given":"Celine","family":"Geywitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew O.","family":"Ellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8740-3688","authenticated-orcid":false,"given":"Tomas","family":"Noli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5185-1898","authenticated-orcid":false,"given":"Amel","family":"Zulji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma C.","family":"Girdler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Kai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-1532","authenticated-orcid":false,"given":"Keying","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly K.","family":"Hoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Gonzalez-Maya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg J.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien M.","family":"Vaquie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Gold Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2489-4825","authenticated-orcid":false,"given":"Riki","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5356-3048","authenticated-orcid":false,"given":"Yu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denny","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Ling","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6709-6666","authenticated-orcid":false,"given":"Staffan","family":"Holmqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Bartels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Ridley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Ja-Yoon","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santos J.","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5381-3801","authenticated-orcid":false,"given":"Eric J.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-3045","authenticated-orcid":false,"given":"Ben","family":"Emery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-3450","authenticated-orcid":false,"given":"Daniel","family":"Geschwind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-4116","authenticated-orcid":false,"given":"Lucas","family":"Schirmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Balmus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-2553","authenticated-orcid":false,"given":"Brian","family":"Popko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2818-8258","authenticated-orcid":false,"given":"Stephen P. J.","family":"Fancy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-0060","authenticated-orcid":false,"given":"David H.","family":"Rowitch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"10310_CR1","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1038\/s41593-018-0221-2","volume":"21","author":"H Fu","year":"2018","unstructured":"Fu, H., Hardy, J. & Duff, K. E. Selective vulnerability in neurodegenerative diseases. Nat. Neurosci. 21, 1350\u20131358 (2018).","journal-title":"Nat. Neurosci."},{"key":"10310_CR2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41586-019-1404-z","volume":"573","author":"L Schirmer","year":"2019","unstructured":"Schirmer, L. et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573, 75\u201382 (2019).","journal-title":"Nature"},{"key":"10310_CR3","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1038\/nrneurol.2012.168","volume":"8","author":"H Lassmann","year":"2012","unstructured":"Lassmann, H., Van Horssen, J. & Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol. 8, 647\u2013656 (2012).","journal-title":"Nat. Rev. Neurol."},{"key":"10310_CR4","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S1474-4422(14)70256-X","volume":"14","author":"DH Mahad","year":"2015","unstructured":"Mahad, D. H., Trapp, B. D. & Lassmann, H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14, 183\u2013193 (2015).","journal-title":"Lancet Neurol."},{"key":"10310_CR5","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/s41586-021-03307-7","volume":"592","author":"B Schumacher","year":"2021","unstructured":"Schumacher, B., Pothof, J., Vijg, J. & Hoeijmakers, J. H. The central role of DNA damage in the ageing process. Nature 592, 695\u2013703 (2021).","journal-title":"Nature"},{"key":"10310_CR6","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41577-022-00751-y","volume":"23","author":"Y Zhao","year":"2023","unstructured":"Zhao, Y., Simon, M., Seluanov, A. & Gorbunova, V. DNA damage and repair in age-related inflammation. Nat. Rev. Immunol. 23, 75\u201389 (2023).","journal-title":"Nat. Rev. Immunol."},{"key":"10310_CR7","doi-asserted-by":"publisher","first-page":"a025130","DOI":"10.1101\/cshperspect.a025130","volume":"5","author":"S Maynard","year":"2015","unstructured":"Maynard, S., Fang, E. F., Scheibye-Knudsen, M., Croteau, D. L. & Bohr, V. A. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb. Perspect. Med. 5, a025130 (2015).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"10310_CR8","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1056\/NEJMra1401483","volume":"378","author":"D Reich","year":"2018","unstructured":"Reich, D., Lucchinetti, C. F. & Calabresi, P. A. Multiple sclerosis. N. Engl. J. Med. 378, 169\u2013180 (2018).","journal-title":"N. Engl. J. Med."},{"key":"10310_CR9","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/s41582-023-00838-7","volume":"19","author":"R Magliozzi","year":"2023","unstructured":"Magliozzi, R., Howell, O. W., Calabrese, M. & Reynolds, R. Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis. Nat. Rev. Neurol. 19, 461\u2013476 (2023).","journal-title":"Nat. Rev. Neurol."},{"key":"10310_CR10","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1016\/j.amjmed.2020.05.049","volume":"133","author":"SL Hauser","year":"2020","unstructured":"Hauser, S. L. & Cree, B. A. Treatment of multiple sclerosis: a review. Am. J. Med. 133, 1380\u20131390 (2020).","journal-title":"Am. J. Med."},{"key":"10310_CR11","doi-asserted-by":"publisher","first-page":"824926","DOI":"10.3389\/fneur.2022.824926","volume":"13","author":"JH Yang","year":"2022","unstructured":"Yang, J. H., Rempe, T., Whitmire, N., Dunn-Pirio, A. & Graves, J. S. Therapeutic advances in multiple sclerosis. Front. Neurol. 13, 824926 (2022).","journal-title":"Front. Neurol."},{"key":"10310_CR12","doi-asserted-by":"publisher","first-page":"2953","DOI":"10.3390\/cancers13122953","volume":"13","author":"ZM Ramdzan","year":"2021","unstructured":"Ramdzan, Z. M., Vickridge, E., Faraco, C. C. & Nepveu, A. CUT domain proteins in DNA repair and cancer. Cancers 13, 2953 (2021).","journal-title":"Cancers"},{"key":"10310_CR13","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41586-018-0453-z","volume":"561","author":"M Munschauer","year":"2018","unstructured":"Munschauer, M. et al. The NORAD lncRNA assembles a topoisomerase complex critical for genome stability. Nature 561, 132\u2013136 (2018).","journal-title":"Nature"},{"key":"10310_CR14","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1128\/MCB.21.5.1719-1729.2001","volume":"21","author":"L Anderson","year":"2001","unstructured":"Anderson, L., Henderson, C. & Adachi, Y. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol. Cell. Biol. 21, 1719\u20131729 (2001).","journal-title":"Mol. Cell. Biol."},{"key":"10310_CR15","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/leu.2010.6","volume":"24","author":"L Mah","year":"2010","unstructured":"Mah, L., El-Osta, A. & Karagiannis, T. \u03b3H2AX: a sensitive molecular marker of DNA damage and repair. Leukemia 24, 679\u2013686 (2010).","journal-title":"Leukemia"},{"key":"10310_CR16","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1007\/s00018-013-1555-2","volume":"71","author":"S Solier","year":"2014","unstructured":"Solier, S. & Pommier, Y. The nuclear \u03b3-H2AX apoptotic ring: implications for cancers and autoimmune diseases. Cell. Mol. Life Sci. 71, 2289\u20132297 (2014).","journal-title":"Cell. Mol. Life Sci."},{"key":"10310_CR17","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/nn.4193","volume":"19","author":"M Traka","year":"2016","unstructured":"Traka, M., Podojil, J. R., McCarthy, D. P., Miller, S. D. & Popko, B. Oligodendrocyte death results in immune-mediated CNS demyelination. Nat. Neurosci. 19, 65\u201374 (2016).","journal-title":"Nat. Neurosci."},{"key":"10310_CR18","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.1093\/brain\/awq247","volume":"133","author":"M Traka","year":"2010","unstructured":"Traka, M. et al. A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain 133, 3017\u20133029 (2010).","journal-title":"Brain"},{"key":"10310_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-016-0312-9","volume":"4","author":"J Mata-Garrido","year":"2016","unstructured":"Mata-Garrido, J., Casafont, I., Tapia, O., Berciano, M. T. & Lafarga, M. Neuronal accumulation of unrepaired DNA in a novel specific chromatin domain: structural, molecular and transcriptional characterization. Acta Neuropathol. Commun. 4, 41 (2016).","journal-title":"Acta Neuropathol. Commun."},{"key":"10310_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53429-5","volume":"15","author":"GJ Duncan","year":"2024","unstructured":"Duncan, G. J. et al. Remyelination protects neurons from DLK-mediated neurodegeneration. Nat. Commun. 15, 9148 (2024).","journal-title":"Nat. Commun."},{"key":"10310_CR21","doi-asserted-by":"publisher","unstructured":"Xia, W. et al. Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair. Nature https:\/\/doi.org\/10.1038\/s41586-026-10290-4 (2026).","DOI":"10.1038\/s41586-026-10290-4"},{"key":"10310_CR22","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav7188","volume":"365","author":"International Multiple Sclerosis Genetics Consortium.","year":"2019","unstructured":"International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019).","journal-title":"Science"},{"key":"10310_CR23","doi-asserted-by":"publisher","first-page":"zcaa022","DOI":"10.1093\/narcan\/zcaa022","volume":"2","author":"R Dueva","year":"2020","unstructured":"Dueva, R. & Iliakis, G. Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond. NAR Cancer 2, zcaa022 (2020).","journal-title":"NAR Cancer"},{"key":"10310_CR24","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.gene.2004.11.008","volume":"344","author":"H Gingras","year":"2005","unstructured":"Gingras, H., Cases, O., Krasilnikova, M., B\u00e9rub\u00e9, G. & Nepveu, A. Biochemical characterization of the mammalian Cux2 protein. Gene 344, 273\u2013285 (2005).","journal-title":"Gene"},{"key":"10310_CR25","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s11011-020-00624-0","volume":"36","author":"Y Akyuva","year":"2021","unstructured":"Akyuva, Y., Naz\u0131ro\u011flu, M. & Y\u0131ld\u0131zhan, K. Selenium prevents interferon-gamma induced activation of TRPM2 channel and inhibits inflammation, mitochondrial oxidative stress, and apoptosis in microglia. Metab. Brain Dis. 36, 285\u2013298 (2021).","journal-title":"Metab. Brain Dis."},{"key":"10310_CR26","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1007\/s11064-013-1123-z","volume":"38","author":"WS Sheng","year":"2013","unstructured":"Sheng, W. S., Hu, S., Feng, A. & Rock, R. B. Reactive oxygen species from human astrocytes induced functional impairment and oxidative damage. Neurochem. Res. 38, 2148\u20132159 (2013).","journal-title":"Neurochem. Res."},{"key":"10310_CR27","doi-asserted-by":"publisher","first-page":"e0162497","DOI":"10.1371\/journal.pone.0162497","volume":"11","author":"NG Spencer","year":"2016","unstructured":"Spencer, N. G., Schilling, T., Miralles, F. & Eder, C. Mechanisms underlying interferon-\u03b3-induced priming of microglial reactive oxygen species production. PLoS ONE 11, e0162497 (2016).","journal-title":"PLoS ONE"},{"key":"10310_CR28","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.pneurobio.2017.05.003","volume":"156","author":"S Monteiro","year":"2017","unstructured":"Monteiro, S., Roque, S., Marques, F., Correia-Neves, M. & Cerqueira, J. J. Brain interference: revisiting the role of IFN\u03b3 in the central nervous system. Prog. Neurobiol. 156, 149\u2013163 (2017).","journal-title":"Prog. Neurobiol."},{"key":"10310_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51906-5","volume":"15","author":"AA Polyzos","year":"2024","unstructured":"Polyzos, A. A. et al. Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain. Nat. Commun. 15, 7726 (2024).","journal-title":"Nat. Commun."},{"key":"10310_CR30","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s00401-020-02258-z","volume":"141","author":"L Zoupi","year":"2021","unstructured":"Zoupi, L. et al. Selective vulnerability of inhibitory networks in multiple sclerosis. Acta Neuropathol. 141, 415\u2013429 (2021).","journal-title":"Acta Neuropathol."},{"key":"10310_CR31","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.freeradbiomed.2022.09.027","volume":"193","author":"Y Anusha-Kiran","year":"2022","unstructured":"Anusha-Kiran, Y. et al. Regional heterogeneity in mitochondrial function underlies region specific vulnerability in human brain ageing: Implications for neurodegeneration. Free Radic. Biol. Med. 193, 34\u201357 (2022).","journal-title":"Free Radic. Biol. Med."},{"key":"10310_CR32","doi-asserted-by":"publisher","first-page":"138","DOI":"10.3389\/fnmol.2016.00138","volume":"9","author":"R Cabr\u00e9","year":"2016","unstructured":"Cabr\u00e9, R. et al. Specific metabolomics adaptations define a differential regional vulnerability in the adult human cerebral cortex. Front. Mol. Neurosci. 9, 138 (2016).","journal-title":"Front. Mol. Neurosci."},{"key":"10310_CR33","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.1093\/brain\/awt110","volume":"136","author":"MT Fischer","year":"2013","unstructured":"Fischer, M. T. et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain 136, 1799\u20131815 (2013).","journal-title":"Brain"},{"key":"10310_CR34","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S0022-510X(00)00343-9","volume":"177","author":"F Lu","year":"2000","unstructured":"Lu, F. et al. Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J. Neurol. Sci. 177, 95\u2013103 (2000).","journal-title":"J. Neurol. Sci."},{"key":"10310_CR35","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1177\/135245859800400503","volume":"4","author":"O Vladimirova","year":"1998","unstructured":"Vladimirova, O. et al. Oxidative damage to DNA in plaques of MS brains. Mult. Scler. 4, 413\u2013418 (1998).","journal-title":"Mult. Scler."},{"key":"10310_CR36","doi-asserted-by":"publisher","unstructured":"Motyer, A. et al. Neuronal somatic mutations are increased in multiple sclerosis lesions. Nat. Neurosci. https:\/\/doi.org\/10.1038\/s41593-025-01895-5 (2025).","DOI":"10.1038\/s41593-025-01895-5"},{"key":"10310_CR37","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.cell.2022.12.027","volume":"186","author":"J-H Yang","year":"2023","unstructured":"Yang, J.-H. et al. Loss of epigenetic information as a cause of mammalian aging. Cell 186, 305\u2013326 (2023).","journal-title":"Cell"},{"key":"10310_CR38","doi-asserted-by":"publisher","first-page":"22520","DOI":"10.1074\/jbc.M115.651042","volume":"290","author":"R Pal","year":"2015","unstructured":"Pal, R. et al. CUX2 protein functions as an accessory factor in the repair of oxidative DNA damage. J. Biol. Chem. 290, 22520\u201322531 (2015).","journal-title":"J. Biol. Chem."},{"key":"10310_CR39","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202051851","volume":"22","author":"E Komulainen","year":"2021","unstructured":"Komulainen, E. et al. Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures. EMBO Rep. 22, e51851 (2021).","journal-title":"EMBO Rep."},{"key":"10310_CR40","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1038\/s41431-018-0184-5","volume":"26","author":"M Barington","year":"2018","unstructured":"Barington, M., Risom, L., Ek, J., Uldall, P. & Ostergaard, E. A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder. Eur. J. Hum. Genet. 26, 1388\u20131391 (2018).","journal-title":"Eur. J. Hum. Genet."},{"key":"10310_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-10715-w","volume":"12","author":"T Suzuki","year":"2022","unstructured":"Suzuki, T. et al. CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate. Sci. Rep. 12, 6505 (2022).","journal-title":"Sci. Rep."},{"key":"10310_CR42","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.cmet.2020.05.019","volume":"32","author":"C Mukherjee","year":"2020","unstructured":"Mukherjee, C. et al. Oligodendrocytes provide antioxidant defense function for neurons by secreting ferritin heavy chain. Cell Metab. 32, 259\u2013272 (2020).","journal-title":"Cell Metab."},{"key":"10310_CR43","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/nrn3900","volume":"16","author":"M Calabrese","year":"2015","unstructured":"Calabrese, M. et al. Exploring the origins of grey matter damage in multiple sclerosis. Nat. Rev. Neurosci. 16, 147\u2013158 (2015).","journal-title":"Nat. Rev. Neurosci."},{"key":"10310_CR44","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1146\/annurev.neuro.30.051606.094313","volume":"31","author":"BD Trapp","year":"2008","unstructured":"Trapp, B. D. & Nave, K.-A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247\u2013269 (2008).","journal-title":"Annu. Rev. Neurosci."},{"key":"10310_CR45","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s40478-020-00938-1","volume":"8","author":"RE James","year":"2020","unstructured":"James, R. E. et al. Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration. Acta Neuropathol. Commun. 8, 66 (2020).","journal-title":"Acta Neuropathol. Commun."},{"key":"10310_CR46","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1007\/s00401-021-02293-4","volume":"141","author":"L van Olst","year":"2021","unstructured":"van Olst, L. et al. Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration. Acta Neuropathol. 141, 881\u2013899 (2021).","journal-title":"Acta Neuropathol."},{"key":"10310_CR47","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65469","volume":"10","author":"Y Chen","year":"2021","unstructured":"Chen, Y., Kunjamma, R. B., Weiner, M., Chan, J. R. & Popko, B. Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment. eLife 10, e65469 (2021).","journal-title":"eLife"},{"key":"10310_CR48","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000374","volume":"4","author":"R Spain","year":"2017","unstructured":"Spain, R. et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol. Neuroimmunol. Neuroinflamm. 4, e374 (2017).","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"10310_CR49","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3389\/fneur.2020.00088","volume":"11","author":"DA Monti","year":"2020","unstructured":"Monti, D. A. et al. N-acetyl cysteine administration is associated with increased cerebral glucose metabolism in patients with multiple sclerosis: an exploratory study. Front. Neurol. 11, 88 (2020).","journal-title":"Front. Neurol."},{"key":"10310_CR50","doi-asserted-by":"crossref","unstructured":"Engelenburg, H. J. et al. Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation. iScience 28, 112430 (2025).","DOI":"10.1016\/j.isci.2025.112430"},{"key":"10310_CR51","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/s41586-023-06250-x","volume":"619","author":"International Multiple Sclerosis Genetics Consortium & Multiple MS Consortium.","year":"2023","unstructured":"International Multiple Sclerosis Genetics Consortium & Multiple MS Consortium. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature 619, 323\u2013331 (2023).","journal-title":"Nature"},{"key":"10310_CR52","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/gene.20162","volume":"43","author":"A Ivanova","year":"2005","unstructured":"Ivanova, A. et al. In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A. Genesis 43, 129\u2013135 (2005).","journal-title":"Genesis"},{"key":"10310_CR53","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1002\/gene.10154","volume":"35","author":"NH Doerflinger","year":"2003","unstructured":"Doerflinger, N. H., Macklin, W. B. & Popko, B. Inducible site-specific recombination in myelinating cells. Genesis 35, 63\u201372 (2003).","journal-title":"Genesis"},{"key":"10310_CR54","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1093\/brain\/awl044","volume":"129","author":"W Lin","year":"2006","unstructured":"Lin, W. et al. Interferon-\u03b3 inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain 129, 1306\u20131318 (2006).","journal-title":"Brain"},{"key":"10310_CR55","doi-asserted-by":"publisher","first-page":"10074","DOI":"10.1523\/JNEUROSCI.2604-04.2004","volume":"24","author":"W Lin","year":"2004","unstructured":"Lin, W. et al. Interferon-\u03b3 induced medulloblastoma in the developing cerebellum. J. Neurosci. 24, 10074\u201310083 (2004).","journal-title":"J. Neurosci."},{"key":"10310_CR56","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.neuron.2011.01.003","volume":"69","author":"SJ Franco","year":"2011","unstructured":"Franco, S. J., Martinez-Garay, I., Gil-Sanz, C., Harkins-Perry, S. R. & M\u00fcller, U. Reelin regulates cadherin function via Dab1\/Rap1 to control neuronal migration and lamination in the neocortex. Neuron 69, 482\u2013497 (2011).","journal-title":"Neuron"},{"key":"10310_CR57","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/j.neuron.2015.04.019","volume":"86","author":"C Gil-Sanz","year":"2015","unstructured":"Gil-Sanz, C. et al. Lineage tracing using Cux2-cre and Cux2-CreERT2 mice. Neuron 86, 1091\u20131099 (2015).","journal-title":"Neuron"},{"key":"10310_CR58","doi-asserted-by":"publisher","first-page":"27290","DOI":"10.1074\/jbc.M112.374777","volume":"287","author":"SM Ebert","year":"2012","unstructured":"Ebert, S. M. et al. Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. J. Biol. Chem. 287, 27290\u201327301 (2012).","journal-title":"J. Biol. Chem."},{"key":"10310_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15851-3","volume":"11","author":"X Li","year":"2020","unstructured":"Li, X. et al. Deep learning enables accurate clustering with batch effect removal in single-cell RNA-seq analysis. Nat. Commun. 11, 2338 (2020).","journal-title":"Nat. Commun."},{"key":"10310_CR60","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).","journal-title":"Genome Biol."},{"key":"10310_CR61","doi-asserted-by":"publisher","first-page":"3222","DOI":"10.1016\/j.cell.2021.04.021","volume":"184","author":"Z Yao","year":"2021","unstructured":"Yao, Z. et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell 184, 3222\u20133241 (2021).","journal-title":"Cell"},{"key":"10310_CR62","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.cell.2018.06.021","volume":"174","author":"A Zeisel","year":"2018","unstructured":"Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999\u20131014 (2018).","journal-title":"Cell"},{"key":"10310_CR63","doi-asserted-by":"crossref","unstructured":"Akhmedov, M., Martinelli, A., Geiger, R. & Kwee, I. Omics Playground: a comprehensive self-service platform for visualization, analytics and exploration of big omics data. NAR Genomics Bioinform. 2, lqz019 (2020).","DOI":"10.1093\/nargab\/lqz019"},{"key":"10310_CR64","doi-asserted-by":"publisher","first-page":"W191","DOI":"10.1093\/nar\/gkz369","volume":"47","author":"U Raudvere","year":"2019","unstructured":"Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191\u2013W198 (2019).","journal-title":"Nucleic Acids Res."},{"key":"10310_CR65","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu, G., Wang, L.-G., Han, Y. & He, Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics 16, 284\u2013287 (2012).","journal-title":"Omics"},{"key":"10310_CR66","doi-asserted-by":"crossref","unstructured":"Friedberg, E. C., Walker, G. C., Siede, W. & Wood, R. D. DNA Repair and Mutagenesis (American Society for Microbiology Press, 2005).","DOI":"10.1128\/9781555816704"},{"key":"10310_CR67","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nrc2998","volume":"11","author":"SS Lange","year":"2011","unstructured":"Lange, S. S., Takata, K. -i & Wood, R. D. DNA polymerases and cancer. Nat. Rev. Cancer 11, 96\u2013110 (2011).","journal-title":"Nat. Rev. Cancer"},{"key":"10310_CR68","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1126\/science.1056154","volume":"291","author":"RD Wood","year":"2001","unstructured":"Wood, R. D., Mitchell, M., Sgouros, J. & Lindahl, T. Human DNA repair genes. Science 291, 1284\u20131289 (2001).","journal-title":"Science"},{"key":"10310_CR69","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nature10424","volume":"478","author":"K Yusa","year":"2011","unstructured":"Yusa, K. et al. Targeted gene correction of \u03b11-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391\u2013394 (2011).","journal-title":"Nature"},{"key":"10310_CR70","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1093\/nar\/gkad1196","volume":"52","author":"E Rajendra","year":"2024","unstructured":"Rajendra, E. et al. Quantitative, titratable and high-throughput reporter assays to measure DNA double strand break repair activity in cells. Nucleic Acids Res. 52, 1736\u20131752 (2024).","journal-title":"Nucleic Acids Res."},{"key":"10310_CR71","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.neuron.2010.04.038","volume":"66","author":"B Cubelos","year":"2010","unstructured":"Cubelos, B. et al. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. Neuron 66, 523\u2013535 (2010).","journal-title":"Neuron"},{"key":"10310_CR72","doi-asserted-by":"publisher","unstructured":"Morcom, L. et al. Data for \u2018DNA damage burden causes selective CUX2 neuron loss in neuroinflammation\u2019. Zenodo https:\/\/doi.org\/10.5281\/zenodo.18489557 (2026).","DOI":"10.5281\/zenodo.18489557"},{"key":"10310_CR73","doi-asserted-by":"publisher","unstructured":"Morcom, L. et al. Data for \u2018DNA damage burden causes selective CUX2 neuron loss in neuroinflammation\u2019. Zenodo https:\/\/doi.org\/10.5281\/zenodo.18022784 (2026).","DOI":"10.5281\/zenodo.18022784"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10310-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10310-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10310-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T12:03:22Z","timestamp":1779278602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10310-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":73,"journal-issue":{"issue":"8115","published-print":{"date-parts":[[2026,5,21]]}},"alternative-id":["10310"],"URL":"https:\/\/doi.org\/10.1038\/s41586-026-10310-3","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"assertion":[{"value":"30 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Y.S. is an employee of Artios Pharma but was previously employed by the University of Cambridge when the work was completed. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}