Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both and . Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.

中文翻译：

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硒蛋白 I 对于醚脂稳态和正常髓鞘形成是不可或缺的


硒蛋白 I (SELENOI) 催化肯尼迪途径的 CDP-乙醇胺分支的最终反应，生成磷脂磷脂酰乙醇胺 (PE) 和纤浆酰-PE。 Plasmenyl-PE 是髓磷脂的关键成分，其特点是具有优先与氧化剂反应的乙烯基醚键，从而充当牺牲性抗氧化剂。在人类中，影响纤浆基-PE 代谢的基因中的多个功能丧失突变与遗传性痉挛性截瘫有关，包括 SELENOI。在此，我们开发了一种神经系统限制性 SELENOI 缺陷的小鼠模型，该模型规避了由组成性缺失引起的胚胎致死，并概括了遗传性痉挛性截瘫的表型特征。由此产生的小鼠表现出脑脂质成分的显着改变，这与运动缺陷和神经病理学相一致，包括髓鞘形成不足、反应性神经胶质增生升高和小头畸形。进一步的研究表明，少突胶质细胞谱系细胞中的脂质过氧化增加，并破坏了少突胶质细胞的成熟。总而言之，这些发现详细说明了 SELENOI 衍生的纤浆烯基-PE 在髓鞘形成中的关键作用，这对于神经发育至关重要。