Neuroprotective effect of neuron‐specific deletion of the <scp>C16</scp> ceramide synthetic enzymes in an animal model of multiple sclerosis

Ceramide C16 is a sphingolipid detected at high levels in several neurodegenerative disorders, including multiple sclerosis (MS). It can be generated de novo or from the hydrolysis of other sphingolipids, such as sphingomyelin or through the recycling of sphingosine, in what is known as the salvage pathway. While the myelin damage occurring in MS suggests the importance of the hydrolytic and salvage pathways, the growing interest on the importance of diet in demyelinating disorders, prompted us to investigate the involvement of de novo ceramide C16 synthesis on disease severity. A diet rich in saturated fats such as palmitic acid, as found in many highly processed foods, provides substrates for the ceramide C16 synthetic enzymes ceramide synthase 6 (CERS6) and 5 (CERS5), which are expressed in the central nervous system. Using the experimental autoimmune encephalomyelitis (EAE) model of inflammatory demyelination, we show here that mice with CamK2a+ neuronal specific deletion of both CerS6 and CerS5 show a milder course of EAE than wild type mice, even when fed a diet enriched in palmitic acid. At a cellular level, neurons lacking both CerS6 and CerS5 are protected from the mitochondrial dysfunction arising from exposure to oxidative stress and palmitic acid in the medium. These data underscore the importance of a healthy diet avoiding processed foods for demyelinating disorders and identifies endogenous neuronal synthesis of ceramide C16 as an important determinant of disease severity.