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This study analyzes the nuclear lipidome in motor neurons in ALS and examines molecular pathways linked to the major lipid alterations. Nuclei were obtained from the frozen anterior horn of the lumbar spinal cord of ALS patients and age\u2010matched controls. Lipidomic profiles of this subcellular fraction were obtained using liquid chromatography and mass spectrometry. We validated the mechanisms behind presumable lipidomic changes by exploring ALS surrogate models including human motor neurons (derived from ALS lines and controls) subjected to oxidative stress, the h<jats:italic>SOD\u2010G93A<\/jats:italic> transgenic mice, and samples from an independent cohort of ALS patients. Among the differential lipid species, we noted 41 potential identities, mostly belonging to phospholipids (particularly ether phospholipids, as plasmalogens), as well as diacylglycerols and triacylglycerides. Decreased expression of alkyldihydroxyacetonephosphate synthase (<jats:italic>AGPS<\/jats:italic>)\u2014a critical peroxisomal enzyme in plasmalogen synthesis\u2014is found in motor neuron disease models; this occurs in parallel with an increase in the expression of sterol carrier protein 2 (<jats:italic>SCP2<\/jats:italic>) mRNA in ALS and Scp2 levels in G93A transgenic mice. Further, we identified diminished expression of diacylglycerol\u2010related enzymes, such as phospholipase C \u03b2I (<jats:italic>PLC\u03b2I<\/jats:italic>) and protein kinase C\u03b2II (<jats:italic>PKC\u03b2II<\/jats:italic>), linked to diacylglycerol metabolism. Finally, lipid droplets were recognized in the nuclei, supporting the identification of triacylglycerides as differential lipids. Our results point to the potentially pathogenic role of altered composition of nuclear membrane lipids and lipids in the nucleoplasm in the anterior horn of the spinal cord in ALS. Overall, these data support the usefulness of subcellular lipidomics applied to neurodegenerative diseases.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15373-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15373","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T18:14:34Z","timestamp":1619547274000},"page":"482-499","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Nuclear lipidome is altered in amyotrophic lateral sclerosis: A pilot 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Chen C. Dong Y. You C. Wang S. Monroig \u00d3. Tocher D. R. &Li Y.(2021).Regulation of long\u2010chain polyunsaturated fatty acid biosynthesis in teleost fish. 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