New insight in sphingolipid formation reveals neurodegenerative process

New understanding of how a class of lipids called sphingolipids are formed could shed light on mechanisms of epilepsy, dementia and other neurodegenerative diseases, paving the way to new treatment approaches, according to Jackson Laboratory (JAX) researchers and their collaborators.

Sphingolipids come in many forms and have vital functions in the neurons of mammals, including signaling and cell surface protection. The basic building materials for these forms are molecules known as long-chain base substrates (LCBs). Certain genetic mutations lead not only to errors in sphingolipid formation but also to surplus levels of LCBs.

In a paper published in the Proceedings of the National Academy of Sciences, researchers led by JAX Associate Research Scientist Lihong Zhao, Ph.D., showed that buildup of the LCB substrate actually causes neurodegeneration.

Mice with CerS1 mutations cannot efficiently make C18 ceramide, a sphingolipid, in neurons, and exhibit neurodegeneration. Similar mutations in humans result in epilepsy and dementia. When the researchers developed a CerS1 mutant mouse that also expresses CerS2, which is not usually found in neurons, the neurodegeneration did not occur.

They determined that even though CerS2 cannot make C18, the CerS2 “soaked up” the excess LCBs, resulting in normal, wild-type levels of LCBs in the mouse brains.

The researchers also showed that, in vitro, LCBs at the elevated levels observed in the CerS1 mice harmed cultured neurons.

“Accumulation of LCBs, but not the reduction of C18 ceramide or other sphingolipids, is an underlying cause of neuronal death due to CerS1 deficiency,” Zhao says. “These results suggest that addressing LCB accumulation could be a new therapeutic approach for neurodegenerative diseases, as changes of sphinoglipid metabolism have been observed in many diseases such as Alzheimer’s disease, Parkinson’s disease, Lewy body dementia and some lysosomal storage diseases.”

Spassieva et al.: Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency. PNAS Early Edition, May 9, 2016,