{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:30:03Z","timestamp":1793399403577,"version":"4.5.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T00:00:00Z","timestamp":1367366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated (ATM) gene. We have analyzed Drosophila melanogaster ATM mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that ATM mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in ATM mutants. Three lines of evidence indicate that ATM mutations cause neurodegeneration by activating the Nuclear Factor-\u03baB (NF-\u03baB) transcription factor Relish, a key regulator of the Immune deficiency (Imd) IIR signaling pathway. First, the level of upregulation of IIR genes, including Relish target genes, was directly correlated with the level of neurodegeneration in ATM mutants. Second, Relish mutations inhibited upregulation of IIR genes and neurodegeneration in ATM mutants. Third, overexpression of constitutively active Relish in glial cells activated the IIR and caused neurodegeneration. In contrast, we found that Imd and Dif mutations did not affect neurodegeneration in ATM mutants. Imd encodes an activator of Relish in the response to gram-negative bacteria, and Dif encodes an immune responsive NF-\u03baB transcription factor in the Toll signaling pathway. These data indicate that the signal that causes neurodegeneration in ATM mutants activates a specific NF-\u03baB protein and does so through an unknown activator. In summary, these findings suggest that neurodegeneration in human A-T is caused by activation of a specific NF-\u03baB protein in glial cells.<\/jats:p>","DOI":"10.1534\/genetics.113.150854","type":"journal-article","created":{"date-parts":[[2013,3,16]],"date-time":"2013-03-16T04:27:46Z","timestamp":1363408066000},"page":"133-142","source":"Crossref","is-referenced-by-count":108,"title":["The Innate Immune Response Transcription Factor Relish Is Necessary for Neurodegeneration in a\n                    <i>Drosophila<\/i>\n                    Model of Ataxia-Telangiectasia"],"prefix":"10.1093","volume":"194","author":[{"given":"Andrew J","family":"Petersen","sequence":"first","affiliation":[{"name":"Molecular and Cellular Pharmacology Program , University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706"},{"name":"Department of Cell and Regenerative Biology , University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeccah J","family":"Katzenberger","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology , University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Wassarman","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Pharmacology Program , University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706"},{"name":"Department of Cell and Regenerative Biology , University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,1]]},"reference":[{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/j.1365-2567.2009.03225.x","article-title":"Inflammation in neurodegenerative disease.","volume":"129","author":"Amor","year":"2010","journal-title":"Immunology"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1073\/pnas.58.3.1112","article-title":"Behavioral mutants of Drosophila isolated by countercurrent distribution.","volume":"58","author":"Benzer","year":"1967","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1007\/s00018-011-0683-9","article-title":"ATM protein kinase: the linchpin of cellular defenses to stress.","volume":"68","author":"Bhatti","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/dev.118.2.401","article-title":"Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.","volume":"118","author":"Brand","year":"1993","journal-title":"Development"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1080\/09553009414551821","article-title":"Clinical and genetic features of ataxia-telangiectasia.","volume":"66","author":"Bundey","year":"1994","journal-title":"Int. J. Radiat. Biol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"E605","DOI":"10.1073\/pnas.1110666109","article-title":"Alternative pathway of cell death in Drosophila mediated by NF-\u03baB transcription factor Relish.","volume":"109","author":"Chinchore","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"e7436","DOI":"10.1371\/journal.pone.0007436","article-title":"The Imd pathway is involved in antiviral immune responses in Drosophila.","volume":"4","author":"Costa","year":"2009","journal-title":"PLoS ONE"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1016\/j.febslet.2010.05.031","article-title":"Multiple roles of ATM in monitoring and maintaining DNA integrity.","volume":"584","author":"Derheimer","year":"2010","journal-title":"FEBS Lett."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"20853","DOI":"10.1073\/pnas.0906749106","article-title":"The immune response attenuates growth and nutrient storage in Drosophila by reducing insulin signaling.","volume":"106","author":"DiAngelo","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/cdd.2009.185","article-title":"The cleaved-Caspase-3 antibody is a marker of Caspase-9-like DRONC activity in Drosophila.","volume":"17","author":"Fan","year":"2010","journal-title":"Cell Death Differ."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.0962-1075.2004.00491.x","article-title":"The moleskin gene product is essential for Caudal-mediated constitutive antifungal Drosomycin gene expression in Drosophila epithelia.","volume":"13","author":"Han","year":"2004","journal-title":"Insect Mol. Biol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/S1097-2765(00)80392-5","article-title":"Relish, a central factor in the control of humoral but not cellular immunity in Drosophila.","volume":"4","author":"Hedengren","year":"1999","journal-title":"Mol. Cell"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1074\/jbc.C400538200","article-title":"Nuclear translocation of caspase-3 is dependent on its proteolytic activation and recognition of a substrate-like protein(s).","volume":"280","author":"Kamada","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/sj.embor.7400629","article-title":"ATM and the DNA damage response. Workshop on ataxia-telangiectasia and related syndromes.","volume":"7","author":"Lavin","year":"2006","journal-title":"EMBO Rep."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1146\/annurev.immunol.25.022106.141615","article-title":"The host defense of Drosophila melanogaster.","volume":"25","author":"Lemaitre","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrg2563","article-title":"Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants.","volume":"10","author":"Lessing","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1101\/gad.8.15.1787","article-title":"Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion.","volume":"8","author":"Luo","year":"1994","journal-title":"Genes Dev."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/sj.embor.7400210","article-title":"ATM and ataxia telangiectasia.","volume":"5","author":"McKinnon","year":"2004","journal-title":"EMBO Rep."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1139\/G10-067","article-title":"Molecular genetic characterization of Drosophila ATM conserved functional domains.","volume":"53","author":"Pedersen","year":"2010","journal-title":"Genome"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.cub.2005.08.048","article-title":"Drosophila sex peptide stimulates female innate immune system after mating via the Toll and Imd pathways.","volume":"15","author":"Peng","year":"2005","journal-title":"Curr. Biol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"169","DOI":"10.4161\/fly.20999","article-title":"Drosophila innate immune response pathways moonlight in neurodegeneration.","volume":"6","author":"Petersen","year":"2012","journal-title":"Fly"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"E656","DOI":"10.1073\/pnas.1110470109","article-title":"ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila.","volume":"109","author":"Petersen","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1101\/gad.1639608","article-title":"Mutations in String\/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia.","volume":"22","author":"Rimkus","year":"2008","journal-title":"Genes Dev."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S1074-7613(00)80208-3","article-title":"The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila.","volume":"12","author":"Rutschmann","year":"2000","journal-title":"Immunity"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1128\/MCB.24.1.172-185.2004","article-title":"The homeobox gene Caudal regulates constitutive local expression of antimicrobial peptide genes in Drosophila epithelia.","volume":"24","author":"Ryu","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1126\/science.7792600","article-title":"A single ataxia telangiectasia gene with a product similar to PI-3 kinase.","volume":"268","author":"Savitsky","year":"1995","journal-title":"Science"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1212\/WNL.10.7.705","article-title":"Progressive ataxia in childhood with particular reference to ataxia-telangiectasia.","volume":"10","author":"Sedgwick","year":"1960","journal-title":"Neurology"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"15957","DOI":"10.1073\/pnas.0607608103","article-title":"GATA factors participate in tissue-specific immune responses in Drosophila larvae.","volume":"103","author":"Senger","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1006\/dbio.2001.0411","article-title":"Peripheral glia direct axon guidance across the CNS\/PNS transition zone.","volume":"238","author":"Sepp","year":"2001","journal-title":"Dev. Biol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/j.cub.2004.06.056","article-title":"ATM is required for telomere maintenance and chromosome stability during Drosophila development.","volume":"14","author":"Silva","year":"2004","journal-title":"Curr. Biol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.8096091","article-title":"NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway.","volume":"259","author":"Sun","year":"1993","journal-title":"Science"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"e3966","DOI":"10.1371\/journal.pone.0003966","article-title":"The Toll\u2192NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer\u2019s Abeta42 polypeptide in Drosophila.","volume":"3","author":"Tan","year":"2008","journal-title":"PLoS ONE"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4161\/fly.5082","article-title":"Host immune response and differential survival of the sexes in Drosophila.","volume":"1","author":"Taylor","year":"2007","journal-title":"Fly"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/j.1460-2075.1992.tb05042.x","article-title":"The characterization of the promoter of the gene encoding the p50 subunit of NF-kappa B indicates that it participates in its own regulation.","volume":"11","author":"Ten","year":"1992","journal-title":"EMBO J."},{"key":"2023030808352863200_","first-page":"1","article-title":"Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia.","volume":"25","author":"Tzou","year":"2010","journal-title":"Immunity"},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.dci.2008.12.002","article-title":"The N-terminal half of the Drosophila Rel\/NF-kappaB factor Relish, REL-68, constitutively activates transcription of specific Relish target genes.","volume":"33","author":"Wiklund","year":"2009","journal-title":"Dev. Comp. Immunol."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1101\/gad.8.8.981","article-title":"repo encodes a glial-specific homeodomain protein required in the Drosophila nervous system.","volume":"8","author":"Xiong","year":"1994","journal-title":"Genes Dev."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1046\/j.1471-4159.1994.63010041.x","article-title":"Neural specificity of elav expression: defining a Drosophila promoter for directing expression to the nervous system.","volume":"63","author":"Yao","year":"1994","journal-title":"J. Neurochem."},{"key":"2023030808352863200_","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s00109-006-0143-4","article-title":"Multifunctional antimicrobial peptides: therapeutic targets in several human diseases.","volume":"85","author":"Zaiou","year":"2007","journal-title":"J. Mol. Med."}],"container-title":["Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/194\/1\/133\/49450014\/genetics0133.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/194\/1\/133\/49450014\/genetics0133.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T10:47:52Z","timestamp":1715078872000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/194\/1\/133\/6065417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,1]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2013,5,1]]},"published-print":{"date-parts":[[2013,5,1]]}},"URL":"https:\/\/doi.org\/10.1534\/genetics.113.150854","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,5,1]]},"published":{"date-parts":[[2013,5,1]]}}}