Deciphering the role of sphingosine 1‐phosphate in central nervous system myelination and repair

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fatima Binish, Junhua Xiao
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Abstract

Sphingosine 1‐phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1‐phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein‐coupled S1P receptors 1–5 (S1PR1–5). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P‐S1PR signalling protects myelin‐forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P–S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation.image
解密 1-磷酸鞘氨醇在中枢神经系统髓鞘化和修复中的作用
1-phosphate 神经鞘氨醇(S1P)是鞘脂家族的一种生物活性脂质,在哺乳动物神经系统中发挥着关键作用。事实上,S1P 是治疗多发性硬化症等脱髓鞘疾病的靶点。作为相互关联的鞘磷脂代谢网络的一部分,可用于信号传递的 S1P 量在其合成酶(鞘磷脂激酶 1 和 2)和降解酶(1-磷酸鞘磷脂裂解酶)之间保持平衡。S1P 一旦产生,就会通过向五个 G 蛋白偶联 S1P 受体 1-5 (S1PR1-5)家族传递信号来发挥其生物学作用。尽管取得了重大进展,但 S1P 代谢和下游信号在调节髓鞘形成和修复过程中的确切作用在很大程度上仍不明确,并存在一定争议。采用各种模型系统进行的遗传学或药理学研究发现,刺激 S1P-S1PR 信号可在中枢神经系统(CNS)损伤后保护髓鞘形成的少突胶质细胞,并减轻体内脱髓鞘现象。然而,尽管阻断 S1P 的合成能揭示内源性 S1P 在促进中枢神经系统再髓鞘化中的作用,但支持其在哺乳动物中枢神经系统再髓鞘化中发挥作用的证据却很有限。本综述重点总结了目前对 S1P 在中枢神经系统髓鞘形成和修复中作用的认识,讨论了 S1P-S1PR 相互作用的复杂性以及 S1P 生物合成和信号调节健康和受伤哺乳动物中枢神经系统少突胶质细胞髓鞘化的潜在机制,并提出了未来研究的新问题。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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