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Signaling and Regulatory Functions of Bioactive Sphingolipids as Therapeutic Targets in Multiple Sclerosis

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Abstract

Spingolipids (SLs) are an important component of central nervous system (CNS) myelin sheaths and affect the viability of brain cells (oligodendrocytes, neurons and astrocytes) that is determined by signaling mediated by bioactive sphingoids (lyso-SLs). Recent studies indicate that two lipids, ceramide and sphingosine 1-phosphate (S1P), are particularly involved in many human diseases including the autoimmune inflammatory demyelination of multiple sclerosis (MS). In this review we: (1) Discuss possible sources of ceramide in CNS; (2) Summarize the features of the metabolism of S1P and its downstream signaling through G-protein-coupled receptors; (3) Link perturbations in bioactive SLs metabolism to MS neurodegeneration and (4) Compile ceramide and S1P relationships to this process. In addition, we described recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod) as well as proposed intervention to specify critical SL levels that tilt balances of apoptotic/active ceramide versus anti-apoptotic/inactive dihydroceramide that may offer a novel and important therapeutic approach to MS.

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Abbreviations

ASMase:

Acid sphingomyelinase

CDase:

Ceramidase

Cer:

Ceramide

Cer1P:

Ceramide 1-phosphate

CerS:

Ceramide synthase (N-acyl transferase)

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DES:

Dihydroceramide desaturase

DHSph:

Dihydrosphingosine

EAE:

Experimental autoimmune encephalomyelitis

GalCer:

Galactosylceramide

GalCerS:

Galactosylceramide synthase

GlcCer:

Glucosylceramide

GlcCerC:

Glucosylceramide synthase

GM:

Gray matter

GSL:

Glycosphingolipid

KDHR:

3-keto-dihydrosphingosine reductase

KDHSph:

3-keto-dihydrosphingosine

MS:

Multiple sclerosis

NAWM:

Normal appearing white matter

NSMase:

Neutral sphingomyelinase

S1P:

Sphingosine 1-phosphate

SM:

Sphingomyelin

SMase:

Sphingomyelinase

SMS:

Sphingomyelin synthase

SpH:

Sphingosine

SphK1:

Sphingosine kinase 1

SphK2:

Sphingosine kinase 2

Spl:

Sphingosine 1-phosphate lyase

SPP1:

Sphingosine 1-phosphate phosphatase 1

SPP2:

Sphingosine 1-phosphate phosphatase 2

SPT:

Serine palmitoyltransferase

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Acknowledgments

We gratefully acknowledge financial support from the National Multiple Sclerosis Society (NMSS, NY, USA; Award #RG3473), and partial support from NINDS/NIH (NS 115666) (to ELH); from Multiple Sclerosis International Federation (Du Pré Grant) (to MP). The authors thank Mrs. Katarzyna Izydorczyk for her skillful assistance with Figures preparation. We apologize to those authors whose work we were unable to cite because of space limitations.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Molecular Medicine and Genetics, Department of Neurology, Georgia Health Science University, 1120 15th Street, Augusta, GA, 30912-2620, USA

    Maria Podbielska & Edward L. Hogan

  2. Department of Immunochemistry, Ludwik Hirszfeld Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, R. Weigla Street 12, 53-114, Wrocław, Poland

    Maria Podbielska & Hubert Krotkiewski

  3. Department of Microbiology, National University of Ireland Galway, University Road, Galway, Ireland

    Edward L. Hogan

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  1. Maria Podbielska
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  2. Hubert Krotkiewski
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  3. Edward L. Hogan
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Correspondence to Edward L. Hogan.

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Special Issue: In honour of Bob Leeden.

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Podbielska, M., Krotkiewski, H. & Hogan, E.L. Signaling and Regulatory Functions of Bioactive Sphingolipids as Therapeutic Targets in Multiple Sclerosis. Neurochem Res 37, 1154–1169 (2012). https://doi.org/10.1007/s11064-012-0728-y

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  • DOI: https://doi.org/10.1007/s11064-012-0728-y

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