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Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury.
- Source :
-
Brain pathology (Zurich, Switzerland) [Brain Pathol] 2012 Jan; Vol. 22 (1), pp. 41-57. Date of Electronic Publication: 2011 Aug 16. - Publication Year :
- 2012
-
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.<br /> (© 2011 The Authors; Brain Pathology © 2011 International Society of Neuropathology.)
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Animals
Cell Death physiology
Coculture Techniques
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental metabolism
Encephalomyelitis, Autoimmune, Experimental pathology
Female
Humans
Infant, Newborn
Leukomalacia, Periventricular metabolism
Leukomalacia, Periventricular pathology
Male
Mice
Mice, Inbred C57BL
Middle Aged
Multiple Sclerosis metabolism
Multiple Sclerosis pathology
Oligodendroglia drug effects
Oligodendroglia metabolism
Primary Cell Culture
Rats
Rats, Sprague-Dawley
Young Adult
Astrocytes metabolism
Astrocytes pathology
Ceramides adverse effects
Ceramides biosynthesis
Oligodendroglia pathology
Up-Regulation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1750-3639
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Brain pathology (Zurich, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 21615590
- Full Text :
- https://doi.org/10.1111/j.1750-3639.2011.00501.x