Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases. In an animal model for cutaneous contact hypersensitivity, we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase-deficient mice, which have increased levels of the endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated allergic inflammation, whereas receptor agonists attenuated inflammation. These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin and suggest a target for therapeutic intervention.
Synthesis of dihydroceramide is catalyzed by a family of (dihydro)ceramide synthases (CerS), first identified in yeast as longevity-assurance genes. Six members (CerS1-6; Lass1-6) of this gene family have been identified in mammals. We examined expression of CerS genes during postnatal development in mouse brain by means of Northern blot analysis, real-time RT-PCR, and in situ-hybridization. In situ-hybridization experiments showed that CerS1 was the predominant CerS in neurons throughout the brain. This observation is in line with the high levels of C18:0-ceramide in neurons and the substrate specificity of CerS1. A similar distribution, but lower expression levels, were found for CerS4 and CerS6. Only low or undetectable amounts of CerS1, CerS4 and CerS6 were, however, present in white matter. In contrast, CerS5 mRNA was detected in most cells within gray and white matter of all brain regions, suggesting ubiquitous expression of this palmitoyl-CoA specific CerS. Expression of CerS2 was transiently increased during the period of active myelination. Furthermore, expression of CerS2 was specifically localized to white matter tracts of the brain. Furthermore, CerS2 was the predominant CerS in Schwann cells of sciatic nerves. These data suggest that CerS2 is important for the synthesis of dihydroceramide used for synthesis of myelin sphingolipids.
Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood. We generated ASPA-deficient (Aspa nur7/nur7 ) mice that are also deficient for NAA synthase Nat8L (Nat8L/Aspa nur7/nur7 ). These mice have no detectable NAA. Nevertheless, they exhibited normal myelin content, myelin sphingolipid composition, and full reversal of spongy myelin and axonal degeneration. Surprisingly, although pathology was fully reversed, the survival time of the mice was not prolonged. In contrast, Aspa nur7/nur7 mice with only one intact Nat8L allele accumulated less NAA, developed a less severe pathology, phenotypic improvements, and, importantly, an almost normal survival time. Therefore, inhibition of NAA synthase is a promising therapeutic option for CD. The reduced survival rate of Nat8L Ϫ/Ϫ /Aspa nur7/nur7 mice, however, indicates that complete inhibition of NAA synthase may bear unforeseeable risks for the patient. Furthermore, we demonstrate that acetate derived from NAA is not essential for myelin lipid synthesis and that loss of NAA-derived acetate does not cause the myelin phenotype of Aspa nur7/nur7 mice. Our data clearly support the hypothesis that NAA accumulation is the major factor in the development of CD.
N-Acetylaspartylglutamate (NAAG) is found at high concentrations in the vertebrate nervous system. NAAG is an agonist at group II metabotropic glutamate receptors. In addition to its role as a neuropeptide, a number of functions have been proposed for NAAG, including a role as a non-excitotoxic transport form of glutamate and a molecular water pump. We recently identified a NAAG synthetase (now renamed NAAG synthetase I, NAAGS-I), encoded by the ribosomal modification protein rimK-like family member B (Rimklb) gene, as a member of the ATP-grasp protein family. We show here that a structurally related protein, encoded by the ribosomal modification protein rimK-like family member A (Rimkla) gene, is another NAAG synthetase (NAAGS-II), which in addition, synthesizes the N-acetylated tripeptide N-acetylaspartylglutamylglutamate (NAAG 2 ). In contrast, NAAG 2 synthetase activity was undetectable in cells expressing NAAGS-I. Furthermore, we demonstrate by mass spectrometry the presence of NAAG 2 in murine brain tissue and sciatic nerves. The highest concentrations of both, NAAG 2 and NAAG, were found in sciatic nerves, spinal cord, and the brain stem, in accordance with the expression level of NAAGS-II. To our knowledge the presence of NAAG 2 in the vertebrate nervous system has not been described before. The physiological role of NAAG 2 , e.g. whether it acts as a neurotransmitter, remains to be determined. N-Acetylaspartylglutamate (NAAG)3 is an abundant peptide in the vertebrate nervous system, found at high micromolar to low millimolar concentrations (1-3). A number of studies demonstrated that NAAG acts as a specific agonist at the group II metabotropic mGluR3 glutamate receptors (4 -6). Agonistic and antagonistic effects of NAAG at N-methyl-D-asparatate receptors have been described (5, 7, 8), but could not be confirmed in later studies (9). Several reports indicate a neuroprotective role of NAAG (10 -12), and in line with this, inhibitors of the NAAG hydrolyzing glutamate carboxypeptidase (GCP)-II have a significant neuroprotective effect in different model systems (13). Increasing NAAG concentrations by GCP-II inhibition appear to reduce glutamate release through activation of presynaptic mGluR3 receptors (for review, see Ref. 13).NAAG may also be involved in neuron-glia signaling (14), although its specific role is not fully understood. Theoretically, synthesis of NAAG could also be an efficient way to transfer large amounts of glutamate from neurons to the extracellular fluid, avoiding the excitotoxic effect of free glutamate (15). A possible role of NAAG as a molecular water pump has also been suggested (16).NAAG is synthesized independently of ribosome from N-acetylaspartate (NAA) and glutamate by NAAG synthetases. Although neurons are the major source of NAAG, it is also present in cultured oligodendrocytes and activated microglia (17). In the mammalian nervous system, the highest NAAG levels have been found in the brain stem, spinal cord, and peripheral nerves (1, 18 -21). NAAG is released from synaptic ...
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