{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:46:45Z","timestamp":1784054805502,"version":"3.55.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020221","name":"Motor Neuron Disease Association Biomedical","doi-asserted-by":"publisher","award":["883-791"],"award-info":[{"award-number":["883-791"]}],"id":[{"id":"10.13039\/501100020221","id-type":"DOI","asserted-by":"publisher"}]},{"name":"V.G. and T.M."},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["GR-2021-12375436"],"award-info":[{"award-number":["GR-2021-12375436"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AriSLA"},{"DOI":"10.13039\/100011776","name":"MND Scotland","doi-asserted-by":"publisher","award":["2021\/MNDS\/RP\/8440GREG"],"award-info":[{"award-number":["2021\/MNDS\/RP\/8440GREG"]}],"id":[{"id":"10.13039\/100011776","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Innate immune signalling pathways are hyperactivated in the CNS of patients with amyotrophic lateral sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1 and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial.<\/jats:p>\n                  <jats:p>Here, we systematically profile type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n = 18), genetic ALS caused by: (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n = 11); and (ii) a SOD1 mutation (SOD1-ALS; n = 5), alongside age- and sex-matched individuals who died of a non-neurological cause (n = 12). Using this deeply phenotyped cohort we have implemented targeted transcriptomic analysis and immunohistochemistry to interrogate the nature and extent of the activation of the type-I IFN response in patients.<\/jats:p>\n                  <jats:p>We determined disease- and genotype-specific IFN signatures that correlate with clinical phenotype. Correlation analysis linked six ISGs with aggressive disease progression, as indicated by negative correlation with age at death in ALS patients. Notably, significant upregulation of ISGs was observed in C9-ALS patients, with higher ISG expression correlating with shorter disease duration. Noting that our genotype- and disease-specific signatures correlated with metrics of disease progression, we explored the therapeutic potential of targeting this pathway in a mouse model of ALS. Treatment with an IFN pathway inhibitor reduced IFN response markers, delayed disease progression, including motor decline, and extended survival in ALS mice.<\/jats:p>\n                  <jats:p>We conclude that upregulation of gene expression in the type-I IFN pathway represents a key pathological feature of ALS and that inhibiting this pathway may provide a promising therapeutic approach for treating ALS.<\/jats:p>","DOI":"10.1093\/brain\/awaf324","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:41:10Z","timestamp":1756899670000},"page":"489-501","source":"Crossref","is-referenced-by-count":5,"title":["Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity"],"prefix":"10.1093","volume":"149","author":[{"given":"Olga","family":"Carletta","sequence":"first","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC) , Rome 00143 ,","place":["Italy"]},{"name":"Department of Science, University \u2018Roma Tre\u2019 , Rome 00146 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Perfetto","sequence":"additional","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC) , Rome 00143 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia M","family":"Rifai","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB ,","place":["UK"]},{"name":"Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Manganelli","sequence":"additional","affiliation":[{"name":"IRCSS Fondazione Santa Lucia, European Center for Brain Research (CERC) , Rome 00143 ,","place":["Italy"]},{"name":"Department of Biology, University of Rome \u2018Tor Vergata\u2019 , Rome 00133 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fergal M","family":"Waldron","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Maniatis","sequence":"additional","affiliation":[{"name":"Zuckerman Institute of Mind Brain and Behavior, Columbia University , New York, NY 10027 ,","place":["USA"]},{"name":"New York Genome Center , New York, NY 10013 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna M","family":"Gregory","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD 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