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The mechanisms underlying the selective degeneration of motor neurons in ALS remain poorly understood, underscoring the need for further investigation into the factors driving this process. In this study, we utilized ALS mouse models and an in\u00a0vitro NSC34 motor neuron cell line expressing the SOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    mutation to identify a novel pathogenic mechanism wherein astrocyte\u2010secreted Tumor necrosis factor\u2010related apoptosis\u2010inducing ligand (TRAIL) binds to Death Receptor 5 (DR5)on motor neurons, leading to caspase\u20108 activation and subsequent neuronal death. Blocking DR5 with neutralizing antibodies significantly attenuated TRAIL\u2010induced motor neuron death. These findings provide the first evidence that TRAIL may serve as a potential therapeutic target in ALS, offering new insights into the mechanisms of motor neuron degeneration in this disease.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70146-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70146","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T07:00:19Z","timestamp":1752217219000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Astrocytes Contribute to Motor Neuron Degeneration in\n       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