title: A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis.
abstract: Maintaining the appropriate complement and content of lipids in cellular membranes is critical for normal neural function. Accumulating evidence suggests that even subtle perturbations in the lipid content of neurons and myelin can disrupt their function and may contribute to myelin and axonal degradation. In this study, we determined the composition and quantified the content of lipids and sterols in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) from control and multiple sclerosis brain tissues by electrospray ionization tandem mass spectrometry. Our results suggest that in active-multiple sclerosis, there is a shift in the lipid composition of NAWM and NAGM to a higher phospholipid and lower sphingolipid content. We found that this disturbance in lipid composition was reduced in NAGM but not in NAWM of inactive-multiple sclerosis. The pattern of disturbance in lipid composition suggests a metabolic defect that causes sphingolipids to be shuttled to phospholipid production. Modelling the biophysical consequence of this change in lipid composition of NAWM indicated an increase in the repulsive force between opposing bilayers that could explain decompaction and disruption of myelin structure.
authors.affiliation: Department of Neurology, Richard T Johnson Division of Neuroimmunology and Neurological Infections, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wheeler
authors.forename: Veera Venkata Ratnam
authors.initials: VV
authors.lastname: Bandaru
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000378:metabolism; D001703:Biophysics; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008563:Membrane Lipids / Q000502:physiology; D008875:Middle Aged; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000378:metabolism*; D009186:Myelin Sheath / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013107:Sphingolipids / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000447:Aldehydes; D008563:Membrane Lipids; D010743:Phospholipids; D013107:Sphingolipids; D002784:Cholesterol
references.citation: Neurology. 2008 Jan 29;70(5):336-43
references.pmid: 17914063
references.citation: J Pharmacol Exp Ther. 2003 Apr;305(1):70-7
references.pmid: 12649354
references.citation: Cell Mol Immunol. 2005 Dec;2(6):439-48
references.pmid: 16426494
references.citation: AJNR Am J Neuroradiol. 2008 Feb;29(2):333-9
references.pmid: 17974617
references.citation: Radiology. 2007 Jul;244(1):249-56
references.pmid: 17522347
references.citation: Biochim Biophys Acta. 2004 Jan 20;1688(1):10-7
references.pmid: 14732476
references.citation: Biochim Biophys Acta. 1976 Jul 15;436(4):900-3
references.pmid: 986174
references.citation: N Engl J Med. 2006 Sep 14;355(11):1124-40
references.pmid: 16971719
references.citation: Ann Neurol. 2004 Feb;55(2):257-67
references.pmid: 14755730
references.citation: Biochim Biophys Acta. 2006 Dec;1758(12):2016-26
references.pmid: 16996023
references.citation: Neuroimage. 2006 Jan 15;29(2):637-42
references.pmid: 16126413
references.citation: J Neuroimmunol. 2004 Aug;153(1-2):108-21
references.pmid: 15265669
references.citation: Brain Res Bull. 2007 Oct 19;74(5):307-16
references.pmid: 17845905
references.citation: Expert Opin Investig Drugs. 2007 Mar;16(3):283-9
references.pmid: 17302523
references.citation: Acta Neurol Scand. 1993 Sep;88(3):174-7
references.pmid: 8256552
references.citation: Proc Natl Acad Sci U S A. 1986 Oct;83(19):7132-6
references.pmid: 3463955
references.citation: J Neurol. 2002 Oct;249(10):1382-90
references.pmid: 12382153
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13466-71
references.pmid: 15353595
references.citation: Exp Mol Pathol. 2007 Oct;83(2):198-206
references.pmid: 17662270
references.citation: Neuroimage. 2005 May 1;25(4):1272-8
references.pmid: 15850745
references.citation: AJNR Am J Neuroradiol. 2007 Aug;28(7):1306-12
references.pmid: 17698533
references.citation: AJNR Am J Neuroradiol. 2007 Sep;28(8):1517-22
references.pmid: 17846203
references.citation: Q Rev Biophys. 1991 Aug;24(3):293-397
references.pmid: 1749824
references.citation: J Pharmacol Exp Ther. 2007 Nov;323(2):469-75
references.pmid: 17682127
references.citation: Biochemistry. 2006 Sep 26;45(38):11247-56
references.pmid: 16981685
references.citation: J Neurol. 2007 Jan;254(1):20-5
references.pmid: 17508137
references.citation: Lab Invest. 1976 Oct;35(4):391-401
references.pmid: 979167
references.citation: Arch Neurol. 2002 Oct;59(10):1565-71
references.pmid: 12374493
references.citation: J Biol Chem. 2002 Jun 14;277(24):21453-7
references.pmid: 11967257
references.citation: Neuropharmacology. 2007 Apr;52(5):1210-8
references.pmid: 17379261
references.citation: Neurology. 2007 May 1;68(18):1481-7
references.pmid: 17470750
references.citation: Nat Med. 1999 Feb;5(2):170-5
references.pmid: 9930864
references.citation: J Neuroimmunol. 2002 Jan;122(1-2):132-9
references.pmid: 11777552
references.citation: J Neuroinflammation. 2006 May 26;3:13
references.pmid: 16729885
references.citation: Biochim Biophys Acta. 2000 Feb 24;1484(1):59-70
references.pmid: 10685031
references.citation: J Neurol. 2008 Jan;255(1):56-63
references.pmid: 18080854
references.citation: Lipids. 1969 Nov;4(6):550-5
references.pmid: 4312744
references.citation: Acta Neurol Scand. 2007 Aug;116(2):100-7
references.pmid: 17661795
references.citation: J Neurosci Res. 1995 Jun 1;41(2):145-52
references.pmid: 7650750
references.citation: Glia. 2007 Dec;55(16):1656-67
references.pmid: 17876806
references.citation: J Neural Transm (Vienna). 2006 Mar;113(3):339-45
references.pmid: 15997419