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Using the <jats:italic>Gnpat<\/jats:italic>\u2010knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter\u2010selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen\u2010deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen\u2010deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin\u2010associated glycoprotein was associated with the active demyelination phase. Using <jats:italic>in vitro<\/jats:italic> myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1\u2010myristyl ether [1\u2010O\u2010tetradecyl glycerol (1\u2010O\u2010TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1\u2010O\u2010TDG treatment rescued myelination in plasmalogen\u2010deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue.<\/jats:p>","DOI":"10.1111\/bpa.12710","type":"journal-article","created":{"date-parts":[[2019,1,23]],"date-time":"2019-01-23T23:53:40Z","timestamp":1548287620000},"page":"622-639","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1\u2010myristyl ether treatment"],"prefix":"10.1111","volume":"29","author":[{"given":"Ana R.","family":"Malheiro","sequence":"first","affiliation":[{"name":"Neurolipid Biology Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade \u2010 i3S, Instituto de Biologia Molecular e Celular \u2013 IBMC e Universidade do Porto Porto Portugal"},{"name":"ICBAS, Instituto Ci\u00eancias Biom\u00e9dicas Abel Salazar Porto 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