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

Somsankar Dasgupta,Swapan K Ray

doi:10.13188/2332-3469.1000035

Abstract

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.

Highlights

Sphingolipids are classified as a group of lipids that contain either a Sphingosine (Sph) or dihydrosphingosine base with a fatty acyl group often attached to the second carbon (C2) atom via -NHCOR linkage [1]
Cer is at the center of many studies for its unique participation in many cellular events including its devastating role in human nervous diseases such as Alzheimer’s disease (AD) and Multiple Sclerosis (MS) while Sph has long been indicated as an inhibitor of Protein Kinase C (PKC) [11,12,13,14]
In support of our theme for this manuscript, we describe the involvement of two other Monoglycosylceramides (MGCs) such as GlcCer and GalCer during Central Nervous System (CNS) development and myelination to further demonstrate the devastating role of Sph in CNS demyelination in course of MS [17]

Summary

Introduction

Sphingolipids are classified as a group of lipids that contain either a Sphingosine (Sph) or dihydrosphingosine (dhSph) base with a fatty acyl group often attached to the second carbon (C2) atom via -NHCOR linkage (designated as ceramide or Cer, where R represents the fatty acyl chain) [1]. Sphingolipids, which include over 4000 bioactive lipid molecules, are significant players in multiple biological processes such as signal transduction, stress responses, immune reaction, membrane structure, and brain development. Cer is at the center of many studies for its unique participation in many cellular events including its devastating role in human nervous diseases such as Alzheimer’s disease (AD) and Multiple Sclerosis (MS) while Sph has long been indicated as an inhibitor of Protein Kinase C (PKC) [11,12,13,14]. Exploration of complex roles of sphingolipids in AD and MS is an active field of investigation. One such recent investigation demonstrated the role of Sph in neurodegeneration in the Central Nervous System (CNS) [15]. The roles of Cer and Sph/ dhSph in CNS development leading to myelination and maturity have not yet been examined

Methods

Results

Conclusion