title: Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury.
abstract: Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis (MS) and periventricular leukomalacia (PVL). Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of MS and PVL, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination, and revealed a concomitant increase of sphingosine and a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor, leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders.
authors: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA.
authors: SunJa
authors: S
authors: Kim
authors: Andrew J
authors: AJ
authors: Steelman
authors: Yumin
authors: Y
authors: Zhang
authors: Hannah C
authors: HC
authors: Kinney
authors: Jianrong
authors: J
authors: Li
references: J Lipid Res. 2002 Dec;43(12):2042-8
references: 12454264
references: J Cardiovasc Pharmacol. 2009 Mar;53(3):198-208
references: 19247196
references: J Neurosci Res. 1996 Feb 01;43(3):382-9
references: 8714527
references: Glia. 2003 Jan 15;41(2):199-206
references: 12509810
references: Pharmacol Ther. 2006 Oct;112(1):171-83
references: 16759708
references: N Engl J Med. 2010 Feb 4;362(5):387-401
references: 20089952
references: J Neurosci Res. 1999 Feb 15;55(4):514-22
references: 10723061
references: J Biol Chem. 2005 Jul 15;280(28):26415-24
references: 15901738
references: Biochim Biophys Acta. 2006 Dec;1758(12):2057-79
references: 16854371
references: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):709-14
references: 12522266
references: J Neurochem. 2011 Jan;116(1):53-66
references: 21044081
references: J Immunol. 2007 Jul 15;179(2):1210-24
references: 17617614
references: FEBS Lett. 1998 Apr 10;426(1):102-6
references: 9598987
references: Immunity. 2010 Mar 26;32(3):414-25
references: 20303295
references: Am J Pathol. 2010 Jun;176(6):2682-94
references: 20413685
references: J Neurosci Res. 2007 Feb 1;85(2):423-32
references: 17086544
references: Ann Neurol. 2002 Oct;52(4):448-57
references: 12325074
references: Glycobiology. 2001 Jun;11(6):451-7
references: 11445550
references: Nat Neurosci. 2001 Jul;4(7):702-10
references: 11426226
references: Brain Pathol. 2001 Jan;11(1):107-16
references: 11145196
references: J Neuroimmunol. 1999 Jul 1;98(1):49-56
references: 10426362
references: Brain Pathol. 1998 Oct;8(4):681-94
references: 9804377
references: J Neurol Sci. 2009 Mar 15;278(1-2):5-15
references: 19147160
references: J Neurosci. 2008 May 14;28(20):5321-30
references: 18480288
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
references: 18216770
references: J Lipid Res. 2010 Jul;51(7):1643-75
references: 20211931
references: Nat Rev Mol Cell Biol. 2003 May;4(5):397-407
references: 12728273
references: Brain Pathol. 2005 Jul;15(3):225-33
references: 16196389
references: Arterioscler Thromb Vasc Biol. 1998 Aug;18(8):1257-65
references: 9714132
references: FASEB J. 2006 Jun;20(8):1152-61
references: 16770014
references: J Biol Chem. 2010 May 7;285(19):14134-43
references: 20215115
references: J Cell Biol. 2009 Dec 14;187(6):761-72
references: 19951898
references: Nat Neurosci. 2004 Oct;7(10):1088-95
references: 15452578
references: Methods Mol Biol. 2009;579:443-67
references: 19763489
references: J Neurosci. 2005 Feb 9;25(6):1459-69
references: 15703400
references: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2070-5
references: 14970312
references: Ann Neurol. 2000 Jun;47(6):707-17
references: 10852536
references: J Neurochem. 2005 Mar;92(5):1204-15
references: 15715670
references: Glia. 2006 Apr 15;53(6):621-30
references: 16470810
references: J Neuropathol Exp Neurol. 2003 May;62(5):441-50
references: 12769184
references: J Neurochem. 2002 Aug;82(4):809-18
references: 12358786
references: Neuron. 2004 Feb 5;41(3):323-35
references: 14766173
references: Am J Pathol. 2004 May;164(5):1673-82
references: 15111314
references: J Immunol. 2002 Jan 1;168(1):298-307
references: 11751974
references: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):751-6
references: 21177428
references: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9936-41
references: 15998743
references: Ann Neurol. 2004 Feb;55(2):257-67
references: 14755730
references: Cell Physiol Biochem. 2010;26(1):41-8
references: 20502003
references: J Neuropathol Exp Neurol. 1988 May;47(3):217-34
references: 3367155
references: FASEB J. 2007 May;21(7):1503-14
references: 17255471
references: Nature. 2004 Jan 22;427(6972):355-60
references: 14737169
references: J Neurosci. 2010 Nov 17;30(46):15400-8
references: 21084596
references: Nat Rev Neurosci. 2002 Sep;3(9):705-14
references: 12209119
references: Cell. 1994 May 6;77(3):325-8
references: 8181053
references: Glia. 2007 Dec;55(16):1656-67
references: 17876806
references: J Neuropathol Exp Neurol. 1987 May;46(3):283-301
references: 3559630
references: Glia. 2010 Sep;58(12):1465-76
references: 20648639
references: Pediatr Res. 2008 Jun;63(6):656-61
references: 18520330
references: Br J Pharmacol. 2004 Nov;143(6):666-84
references: 15504747
references: Cell Death Differ. 2008 Jul;15(7):1178-86
references: 18483490