{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:18:11Z","timestamp":1791296291123,"version":"4.1.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"15","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,4,11]]},"abstract":"<jats:p>\n                    The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    and SOD1\n                    <jats:sup>G85R<\/jats:sup>\n                    , but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas\/NO feedback amplification loop is required for motoneuron death\n                    <jats:italic>in vitro<\/jats:italic>\n                    .\n                    <jats:italic>In vivo<\/jats:italic>\n                    , mutant SOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    and SOD1\n                    <jats:sup>G85R<\/jats:sup>\n                    mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas\/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0508774103","type":"journal-article","created":{"date-parts":[[2006,3,31]],"date-time":"2006-03-31T20:25:44Z","timestamp":1143836744000},"page":"6007-6012","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":104,"title":["Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL"],"prefix":"10.1073","volume":"103","author":[{"given":"C.","family":"Raoul","sequence":"first","affiliation":[{"name":"*Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), Integrative Biosciences Institute, SV IBI LEN, AAB 1 32, CH-1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Buhler","sequence":"additional","affiliation":[{"name":"Institut de Neurobiologie de la M\u00e9diterran\u00e9e (INMED), Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Equipe Avenir, F-13273 Marseille Cedex 09, France;"},{"name":"Universit\u00e9 de la M\u00e9diterran\u00e9e, F-13288 Marseille, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Sadeghi","sequence":"additional","affiliation":[{"name":"*Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), Integrative Biosciences Institute, SV IBI LEN, AAB 1 32, CH-1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Jacquier","sequence":"additional","affiliation":[{"name":"Institut de Neurobiologie de la M\u00e9diterran\u00e9e (INMED), Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Equipe Avenir, F-13273 Marseille Cedex 09, France;"},{"name":"Universit\u00e9 de la M\u00e9diterran\u00e9e, F-13288 Marseille, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Aebischer","sequence":"additional","affiliation":[{"name":"*Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), Integrative Biosciences Institute, SV IBI LEN, AAB 1 32, CH-1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Pettmann","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de la M\u00e9diterran\u00e9e, F-13288 Marseille, France; and"},{"name":"Institut de Biologie du D\u00e9veloppement de Marseille (IBDM), Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Unit\u00e9 Mixte de Recherche 623, F-13288 Marseille Cedex 09, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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