Adult Ceramide Synthase 2 (CERS2)-deficient Mice Exhibit Myelin Sheath Defects, Cerebellar Degeneration, and Hepatocarcinomas

Abstract

(Dihydro)ceramide synthase 2 (cers2, formerly called lass2) is the most abundantly expressed member of the ceramide synthase gene family, which includes six isoforms in mice. CERS2 activity has been reported to be specific toward very long fatty acid residues (C22-C24). In order to study the biological role of CERS2, we have inactivated its coding region in transgenic mice using gene-trapped embryonic stem cells that express lacZ reporter DNA under control of the cers2 promoter. The resulting mice lack ceramide synthase activity toward C24:1 in the brain as well as the liver and show only very low activity toward C18:0 -C22:0 in liver and reduced activity toward C22:0 residues in the brain. In addition, these mice exhibit strongly reduced levels of ceramide species with very long fatty acid residues (>C22) in the liver, kidney, and brain. From early adulthood on, myelin stainability is progressively lost, biochemically accompanied by about 50% loss of compacted myelin and 80% loss of myelin basic protein. Starting around 9 months, both the medullary tree and the internal granular layer of the cerebellum show significant signs of degeneration associated with the formation of microcysts. Predominantly in the peripheral nervous system, we observed vesiculation and multifocal detachment of the inner myelin lamellae in about 20% of the axons. Beyond 7 months, the CERS2-deficient mice developed hepatocarcinomas with local destruction of tissue architecture and discrete gaps in renal parenchyma. Our results indicate that CERS2 activity supports different biological functions: maintenance of myelin, stabilization of the cerebellar as well as renal histological architecture, and protection against hepatocarcinomas.

ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis

“…S7). CERS2 is known to be important for C24 Cer synthesis (3,22). Both of the reactions inhibited by FB 1 or CERS2 siRNA, i.e., the elongations of C20:0-and C22:0-CoAs, are essential for the production of C24-CoA, the CERS2 substrate.…”

“…5). A recent report analyzing CerS2 knockout mice revealed that a deficiency in C24 sphingolipid synthesis results in myelin sheath defects, cerebellar degeneration, and hepatopathy (3,11). Moreover, the VLCFA moiety of sphingolipids may be important for determination in molecular species of sphingolipids, because C24 FAs are used in the gangliosides GM3 and GD3 but not in other gangliosides with more complex sugar structures (27).…”

“…VLCFAs are characteristically divided into saturated, monounsaturated, n-6 polyunsaturated, and n-3 polyunsaturated FAs (PUFAs), each of which exhibit distinct functions and properties. Most saturated and monounsaturated VLCFAs are sphingolipid components and so play important roles in skin barrier formation and neural functions (2,3). PUFAs of the n-6 series (e.g., C20:4) are involved in the promotion of inflammation as precursors of eicosanoids (4).…”

“…Each of six mammalian Cer synthases (CERS1-6) exhibits its own characteristic substrate specificity toward certain fatty acyl-CoA(s) (2). Recent studies using CerS2 knockout mice revealed that CerS2 is the predominant Cer synthase for C24 Cer production (3,10). These mice exhibited severe hepatopathy, myelin sheath defects, and cerebellar degeneration (3,11).…”

“…Recent studies using CerS2 knockout mice revealed that CerS2 is the predominant Cer synthase for C24 Cer production (3,10). These mice exhibited severe hepatopathy, myelin sheath defects, and cerebellar degeneration (3,11).…”