{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T07:46:31Z","timestamp":1780731991662,"version":"3.54.1"},"reference-count":96,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00 NS091486"],"award-info":[{"award-number":["R00 NS091486"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS110385"],"award-info":[{"award-number":["R01 NS110385"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS079702"],"award-info":[{"award-number":["R01 NS079702"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS109150"],"award-info":[{"award-number":["R01 NS109150"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21\u2010NS0103118"],"award-info":[{"award-number":["R21\u2010NS0103118"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 NS116761"],"award-info":[{"award-number":["R21 NS116761"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS051488"],"award-info":[{"award-number":["R01 NS051488"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1\u2010AG057882"],"award-info":[{"award-number":["RF1\u2010AG057882"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genetic mutations that cause amyotrophic lateral sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. In addition to direct defects within motor neurons, growing evidence suggests that dysfunction of non\u2010neuronal cells is also an important driver of disease. Previously, we demonstrated that mutations in DNA\/RNA binding protein fused in sarcoma (FUS) induce neurotoxic phenotypes in astrocytes in vitro<jats:italic>,<\/jats:italic> via activation of the NF\u2010\u03baB pathway and release of pro\u2010inflammatory cytokine TNF\u03b1. Here, we developed an intraspinal cord injection model to test whether astrocyte\u2010specific expression of ALS\u2010causative FUS<jats:sup>R521G<\/jats:sup> variant (mtFUS) causes neuronal damage in vivo. We show that restricted expression of mtFUS in astrocytes is sufficient to induce death of spinal motor neurons leading to motor deficits through upregulation of TNF\u03b1. We further demonstrate that TNF\u03b1 is a key toxic molecule as expression of mtFUS in TNF\u03b1 knockout animals does not induce pathogenic changes. Accordingly, in mtFUS\u2010transduced animals, administration of TNF\u03b1 neutralizing antibodies prevents neurodegeneration and motor dysfunction. Together, these studies strengthen evidence that astrocytes contribute to disease in ALS and establish, for the first time, that FUS\u2010ALS astrocytes induce pathogenic changes to motor neurons in vivo. Our work identifies TNF\u03b1 as the critical driver of mtFUS\u2010astrocytic toxicity and demonstrates therapeutic success of targeting TNF\u03b1 to attenuate motor neuron dysfunction and death. Ultimately, through defining and subsequently targeting this toxic mechanism, we provide a viable FUS\u2010ALS specific therapeutic strategy, which may also be applicable to sporadic ALS where FUS activity and cellular localization are frequently perturbed.<\/jats:p>","DOI":"10.1002\/glia.24183","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T06:41:15Z","timestamp":1651041675000},"page":"1426-1449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Targeting TNF\u03b1 produced by astrocytes expressing amyotrophic lateral sclerosis\u2010linked mutant fused in sarcoma prevents neurodegeneration and motor dysfunction in mice"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-6307","authenticated-orcid":false,"given":"Brigid K.","family":"Jensen","sequence":"first","affiliation":[{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0025-1921","authenticated-orcid":false,"given":"Kevin J.","family":"McAvoy","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolette M.","family":"Heinsinger","sequence":"additional","affiliation":[{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo C.","family":"Lepore","sequence":"additional","affiliation":[{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hristelina","family":"Ilieva","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron R.","family":"Haeusler","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6338-6404","authenticated-orcid":false,"given":"Davide","family":"Trotti","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera","family":"Pasinelli","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41040-4"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00687970"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-012-0396-3"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1067859"},{"issue":"14","key":"e_1_2_9_6_1","first-page":"3080","article-title":"Disruption of the astrocytic TNFR1\u2010GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis","volume":"25","author":"Brambilla L.","year":"2016","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr199"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160520"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80272-X"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2007.10.028"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2020.06.010"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.06.006"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17820"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017187"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2014.78"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1885"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2018100130"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2011.05.002"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.261"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.143"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2017.08.006"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000180"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9010261"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606253113"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.013"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0140-5"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep02388"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-7-33"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1079851"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-02-00660.2000"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70270-3"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0602-06.2006"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10030518"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.023"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-9961(03)00087-1"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.52"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/72842"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlaa003"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.169"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00688335"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-017-0742-1"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23298"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5253-05.2006"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00689827"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2010.03.029"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199105000-00008"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1166066"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.03.010"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4690-13.2014"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000244"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu094"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1933-9"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-5-45"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314085111"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199712000-00006"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1200-z"},{"key":"e_1_2_9_57_1","first-page":"15","article-title":"Clinical limits of amyotrophic lateral sclerosis","volume":"36","author":"Mulder D. W.","year":"1982","journal-title":"Advances in Neurology"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00293379"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1876"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490380312"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-014-0159-6"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.4.1397"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078887"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222361110"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01177-0"},{"issue":"10","key":"e_1_2_9_66_1","first-page":"28","article-title":"Virus\u2010like inclusions in the cells of the central nervous system in amyotrophic lateral sclerosis","volume":"44","author":"Popova L. M.","year":"1982","journal-title":"Arkhiv Patologii"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.03.003"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23003"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21665"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3584"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00486"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.02.003"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1687-9"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2014.07.016"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10465"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4486-04.2005"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04671"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482960802709416"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2016.1267768"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318264f164"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111313"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2010.03.004"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2010.09.001"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.122"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/2985051"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.06.008"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01283-z"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz217"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1429-7"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1165942"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt117"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.12.6821"},{"key":"e_1_2_9_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2014.05.006"},{"key":"e_1_2_9_94_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2015.1055275"},{"key":"e_1_2_9_95_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21167"},{"key":"e_1_2_9_96_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2016.1143012"},{"key":"e_1_2_9_97_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2016-315018"}],"container-title":["Glia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.24183","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/glia.24183","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.24183","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T17:07:15Z","timestamp":1692983235000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/glia.24183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,26]]},"references-count":96,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1002\/glia.24183"],"URL":"https:\/\/doi.org\/10.1002\/glia.24183","archive":["Portico"],"relation":{},"ISSN":["0894-1491","1098-1136"],"issn-type":[{"value":"0894-1491","type":"print"},{"value":"1098-1136","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,26]]},"assertion":[{"value":"2021-12-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}