Abstract
Sphingolipids (SLs) act as signaling molecules and as structural components in both neuronal cells and myelin. We now characterize the biochemical, histological, and behavioral abnormalities in the brain of a mouse lacking very long acyl (C22-C24) chain SLs. This mouse, which is defective in the ability to synthesize C22-C24-SLs due to ablation of ceramide synthase 2, has reduced levels of galactosylceramide (GalCer), a major component of myelin, and in particular reduced levels of non-hydroxy-C22-C24-GalCer and 2-hydroxy-C22-C24- GalCer. Noteworthy brain lesions develop with a time course consistent with a vital role for C22-C24-GalCer in myelin stability. Myelin degeneration and detachment was observed as was abnormal motor behavior originating from a subcortical region. Additional abnormalities included bilateral and symmetrical vacuolization and gliosis in specific brain areas, which corresponded to some extent to the pattern of ceramide synthase 2 expression, with astrogliosis considerably more pronounced than microglial activation. Unexpectedly, unidentified storage materials were detected in lysosomes of astrocytes, reminiscent of the accumulation that occurs in lysosomal storage disorders. Together, our data demonstrate a key role in the brain for SLs containing very long acyl chains and in particular GalCer with a reduction in their levels leading to distinctive morphological abnormalities in defined brain regions.
Highlights
84105, Israel, **School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0230, ‡‡Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine and Tufts Medical Center, Boston, Massachusetts 01536, and §§Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany
CerS2 mRNA expression levels are significantly lower in the whole brain than in the liver [12], it might be expressed at higher levels in a subset of brain cells, such as oligodendrocytes [16], and SLs containing very long acyl chain fatty acids are abundant in white matter and in myelin [17, 18], suggesting a key role for CerS2 in these cells and brain regions
We show that CerS2-null mice exhibit profound alterations in lipid composition in both whole brain and myelin; NBD, 4-nitrobenzo-2-oxa-1,3-diazole; GP, globus pallidus; GFAP, glial fibrillary acidic protein
Summary
From the Departments of ‡Biological Chemistry and §Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel, ¶Department of Human Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel, ʈDepartment of Physiology and Neurobiology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva. We show that CerS2-null mice exhibit profound alterations in lipid composition in both whole brain and myelin; NBD, 4-nitrobenzo-2-oxa-1,3-diazole; GP, globus pallidus; GFAP, glial fibrillary acidic protein. CerS2-null mice exhibit neurological abnormalities originating from a subcortical region and accumulation of unidentified storage materials in lysosomes of astrocytes
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