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Sphingosine Toxicity in EAE and MS: Evidence for Ceramide Generation via Serine-Palmitoyltransferase Activation

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Abstract

Multiple sclerosis (MS) is a demyelinating disorder characterized by massive neurodegeneration and profound axonal loss. Since myelin is enriched with sphingolipids and some of them display toxicity, biological function of sphingolipids in demyelination has been investigated in MS brain tissues. An elevation of sphingosine with a decrease in monoglycosylceramide and psychosine (myelin markers) was observed in MS white matter and plaque compared to normal brain tissue. This indicated that sphingosine toxicity might mediate oligodendrocyte degeneration. To explain the source of sphingosine accumulation, total sphingolipid profile was investigated in Lewis rats after inducing experimental autoimmune encephalomyelitis (EAE) and also in human oligodendrocytes in culture. An intermittent increase in ceramide followed by sphingosine accumulation in EAE spinal cord along with a stimulation of serine-palmitoyltransferase (SPT) activity was observed. Apoptosis was identified in the lumbar spinal cord, the most prominent demyelinating area, in the EAE rats. TNFα and IFNγ stimulation of oligodendrocytes in culture also led to an accumulation of ceramide with an elevation of sphingosine. Ceramide elevation was drastically blocked by myriocin, an inhibitor of SPT, and also by FTY720. Myriocin treatment also protected oligodendrocytes from cytokine mediated apoptosis or programmed cell death. Hence, we propose that sphingosine toxicity may contribute to demyelination in both EAE and MS, and the intermittent ceramide accumulation in EAE may, at least partly, be mediated via SPT activation, which is a novel observation that has not been previously reported.

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Abbreviations

EAE:

Experimental autoimmune encephalomyelitis

FMCs:

Fast migrating cerebrosides

GalCer:

Galactosylceramide

GC-MS:

Gas chromatography-mass spectrometry.

HPLC:

High performance liquid chromatography

HPTLC:

High performance thin-layer chromatography

MGC:

Monoglycosylceramide

MS:

Multiple sclerosis

NAWM:

Normal appearing white matter

SC:

Spinal cord

SPT:

Serine palmitoyltransferase

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Acknowledgements

We thank late Ms. Elaine Terry and Ms. Denise Matzelle for excellent laboratory assistance. This work was supported in part by these grants: NINDS-NS-31355 (SD), NIAAA-11865 (SD), SC State Appropriation # CR22 (SD), NINDS-NS-38146 (NLB), NINDS-NS-41088 (NLB), the National Multiple Sclerosis Society RG-2130 (NLB), NCI-CA-91460 (SKR), NINDS-NS-057811 (SKR), and SC SCIRF-2015-I-0 (SKR). We acknowledge the encouragement and support from Dr. E. L. Hogan, Ex-chair, Department of Neurology, Medical University of South Carolina (MUSC), Charleston, SC, USA and also Dr. David Perry, Department of Biochemistry, MUSC, Charleston, SC, USA for his advice on SPT assay. We acknowledge Prof. E. Bieberich, Augusta University, Augusta, GA, USA for supplying essential reagents and critically reviewing the manuscript.

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    Authors and Affiliations

    1. Department of Neurology and Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA

      Lawrence G. Miller Jr., Jennifer A. Young & Naren L. Banik

    2. Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC, 29209, USA

      Swapan K. Ray

    3. Institute of Molecular Medicine and Genetics, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

      Guanghu Wang & Somsankar Dasgupta

    4. Center for Biotechnology and Genomic Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

      Sharad Purohit

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    Lawrence G. Miller Jr. and Jennifer A. Young contributed equally and were recipients of Summer undergraduate fellowships.

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    Miller, L.G., Young, J.A., Ray, S.K. et al. Sphingosine Toxicity in EAE and MS: Evidence for Ceramide Generation via Serine-Palmitoyltransferase Activation. Neurochem Res 42, 2755–2768 (2017). https://doi.org/10.1007/s11064-017-2280-2

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