神经鞘脂在中枢神经系统中的多种生物学功能:神经酰胺和鞘磷脂调节发育中的脑髓鞘形成,但在多发性硬化症发病过程中刺激脱髓鞘。

Journal of neurology and psychology Pub Date : 2017-12-01 Epub Date: 2017-12-23 DOI:10.13188/2332-3469.1000035
Somsankar Dasgupta, Swapan K Ray
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引用次数: 35

摘要

鞘脂富含中枢神经系统,具有多种生物学功能。它们参与组织发育、细胞识别和粘附,并充当毒素的受体。在髓鞘形成过程中,多种相互作用的分子如髓鞘碱性蛋白、髓鞘相关糖蛋白、磷脂、胆固醇、鞘脂等以复杂的方式参与。一些鞘脂在髓鞘形成中的确切作用仍未被探索。我们的研究描述了几种鞘脂参与大鼠脑发育过程中的髓鞘形成以及多发性硬化症(MS)发病过程中的人脑脱髓鞘。这些鞘脂包括神经酰胺(Cer)/二氢神经酰胺(dhCer)、鞘氨酸(Sph)/二氢鞘氨酸(dhSph)和葡萄糖/半乳糖神经酰胺(glc/galCer),我们通过柱层析、高效薄层色谱、气相色谱-质谱和高效液相色谱检测这些鞘脂。在大鼠大脑发育过程中,Cer/dhCer水平从胚胎期(E)至出生后(P21)开始升高,然后逐渐下降至成熟期(P30及以后),并在整个大脑发育过程中保持稳定的比例(4-4.5:1)。glcer是出生后早期(P8)出现的初始单糖基神经酰胺(MGC), GalCer在P10出现,并呈增加趋势,直至P21,其浓度保持不变。Sph和dhSph的变化趋势相似,在P10出现峰值,在P21出现较小的峰值,Sph:dhSph的比值为(2-2.5:1)。所有这些鞘脂的谱,特别是在P21,清楚地表明它们在大鼠大脑发育中的重要性,但在髓鞘形成中的作用有些不明确。虽然有报道称Cer与阿尔茨海默病和帕金森病等神经退行性疾病有关,但Sph作为蛋白激酶C的有效抑制剂,最近被认为与MS引起的中枢神经系统脱髓鞘有关。炎性细胞因子刺激MS大脑中Sph升高,导致少突胶质细胞死亡导致脱髓鞘,我们通过人类少突胶质细胞培养进行了研究。综上所述,鞘脂对大脑发育至关重要,但它们对脱髓鞘疾病(如多发性硬化症)有有害影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Diverse Biological Functions of Sphingolipids in the CNS: Ceramide and Sphingosine Regulate Myelination in Developing Brain but Stimulate Demyelination during Pathogenesis of Multiple Sclerosis.

Diverse Biological Functions of Sphingolipids in the CNS: Ceramide and Sphingosine Regulate Myelination in Developing Brain but Stimulate Demyelination during Pathogenesis of Multiple Sclerosis.

Diverse Biological Functions of Sphingolipids in the CNS: Ceramide and Sphingosine Regulate Myelination in Developing Brain but Stimulate Demyelination during Pathogenesis of Multiple Sclerosis.

Diverse Biological Functions of Sphingolipids in the CNS: Ceramide and Sphingosine Regulate Myelination in Developing Brain but Stimulate Demyelination during Pathogenesis of Multiple Sclerosis.

Sphingolipids are enriched in the Central Nervous System (CNS) and display multiple biological functions. They participate in tissue development, cell recognition and adhesion, and act as receptors for toxins. During myelination, a variety of interactive molecules such as myelin basic protein, myelin associated glycoprotein, phospholipids, cholesterol, sphingolipids, etc., participate in a complex fashion. Precise roles of some sphingolipids in myelination still remain unexplored. Our investigation delineated participation of several sphingolipids in myelination during rat brain development as well as in human brain demyelination during pathogenesis of Multiple Sclerosis (MS). These sphingolipids included Ceramide (Cer)/dihydroceramide (dhCer), Sphingosine (Sph)/dihydrosphingosine (dhSph), and glucosyl/galactosylceramide (glc/galCer) as we detected these by column chromatography, high performance thin-layer chromatography, gas chromatography-mass spectrometry, and high-performance liquid chromatography. Cer/dhCer level rises during rat brain development starting at Embryonic stage (E) until postnatal day (P21), then gradually falls until the maturity (P30 and onwards), and remains steady maintaining a constant ratio (4-4.5:1) throughout the brain development. GlcCer is the initial Monoglycosylceramide (MGC) that appears at early Postnatal stage (P8) and then GalCer appears at P10 with an increasing trend until P21 and its concentration remains unaltered. Sph and dhSph profiles show a similar trend with an initial peak at P10 and then a comparatively smaller peak at P21 maintaining a ratio of (2-2.5:1) of Sph:dhSph. The profiles of all these sphingolipids, specifically at P21, clearly indicate their importance during rat brain development but somewhat unspecified roles in myelination. While Cer has been reported to involve in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, Sph being a potent inhibitor of protein kinase C has recently been implicated in CNS demyelination due to MS. Inflammatory cytokines stimulate Sph elevation in MS brains and lead to demyelination due to oligodendrocyte death as we examined by using human oligodendroglioma culture. In conclusions, sphingolipids are essential for brain development but they have deleterious effects in demyelinating diseases such as MS.

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