Ceramide homeostasis in the brain

Dawson, G., *Testai, F., Kilkus, J.P. and Qin, J.

Univ of Chicago, Il 60637 and *Univ Illinois, Chicago.

Ceramide (N-acylsphingosine: Cer) has long been associated with programmed cell death in the CNS and elsewhere and the mechanisms governing its homeostasis are complex. Cer can be synthesized de novo by many organisms but in mammals this requires molecular oxygen to convert dihydroceramide (DHC) to Cer.  Hypoxia and stroke inhibit synthesis of Cer and its precursor (DHC) accumulates in brain and CSF. Cer can also be generated in the lysosome by the action of acid sphingomyelinase. The plasma membrane neutral sphingomyelinase (NSMase2) is regulated by palmitoylation and in various stress situations, the Cer generated by NSMase2 in turn activates PP2A phosphatase and inhibits Akt pathways leading to activation of caspase-3, p53, reduced SIRT-1 expression and cell death. Thus the anti-metastatic drug 4MU induces cell death and inhibits migration and invasion in gliomas by activating NSMase2 at the cell surface, increasing Cer and inactivating hyaluronan synthase2. In contrast, cells lacking NSMase2 show reduced Cer and increased hyaluronan synthesis. Cer is further metabolized to sphingosine and then to sphingosine-1-phosphate (S1P) by the action of kinases SK1 and SK2. S1P is considered to be protective to the brain and is reduced in stroke and MS lesions. S1P can be recycled back to sphingosine and then reacylated to ceramide, the ceramide synthase (mainly CerS2) being inhibited by neurotoxins such as Fumonisin B1. The use of MS/MS has greatly increased our ability to track these changes but many questions about ceramide homeostasis in the brain remain to be answered. (Supported by USPHS Grants NS-36866-40 to GD.