University of Kentucky, USA
Molecular phenotyping of CerS1 deficiency in mouse cerebellum
Ceramide synthase 1 (CerS1) is the main neuronal ceramide synthase catalyzing the generation of C18 ceramide. Catalytically inactive mutation of CerS1 results in 50% reduction of brain C18 ceramide and significant increases in sphingoid bases causing Purkinje cell degradation and cerebellar ataxia. Ectopic expression of CerS2 in the neurons of the CerS1 mutant restores sphingoid bases to wild type levels, rescues Purkinje cells from degradation, and eliminates the ataxia phenotype. CerS2 isoform shares the same sphingoid base substrates as CerS1, but catalyzes the production of very long-chain ceramides (C22-C24).
Our recent expression profiles analysis suggest that increased levels of sphingoid bases due to CerS1 deficiency affect the expression of genes critical for the survival and maintenance of cerebellar neurons, such as genes involved in neurogenesis, synaptic functions, and calcium signaling. Proteins with pleckstrin homology or SH3 domains were also affected. In addition, our analyses revealed that CerS1 deficiency in the cerebellum leads to up regulation of the complement system and G-protein coupled receptor signaling. Moreover, our results predict that differences in the sphingolipids’ fatty acyl chain-length produce functionally distinct cerebellar neurons when Cers2 is used to rescue defects caused by CerS1 mutation.