Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.

Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS) is a genetic multi-system disorder mostly affecting infants and children. In infants, SPLIS has a mortality of about 80% within five years of onset. It affects the kidney, adrenal gland (hormone production), neurological system, skin, and immune system. The most severe consequences involve kidney failure, susceptibility to infections, and neurological defects. The reason SPLIS children develop kidney failure is not completely understood. Identifying key signaling pathways and kidney cell types involved in SPLIS kidney disease will help us find new therapeutic strategies and will help determine which cells to target with gene therapy. SPLIS is caused by mutations that inactivate the SGPL1 gene, which codes for an essential enzyme needed for the body to metabolize sphingolipids. In this study, we investigated the biochemical effects of SPLIS by studying the skin cells of an affected infant and by studying mouse models that lack SGPL1 function. Our findings showed some unexpected changes in sphingolipid metabolism that appear to help cells to cope with the lack of enzyme function. They do so by shunting some of the toxic sphingolipids that accumulate into less toxic molecules through metabolic rerouting. SPLIS cells also trigger a feedback mechanism that reduces the production of sphingolipids, thereby dampening the consequences of ineffective sphingolipid metabolism. In human kidney cell models of SPLIS, we found that SPLIS causes changes in the architecture of key kidney cells called proximal tubule cells, contributing to kidney dysfunction and failure. These changes could be blocked in a mouse model of SPLIS by treatment of the mice with a drug called fasudil, an inhibitor of the ROCK enzyme, which controls cell architecture. These findings help us understand how kidney failure occurs in SPLIS children and which cells of the kidney are affected by disruption of sphingolipid metabolism. The information we gained tells us that proximal tubule cells should be included in the type of kidney cells we should target with SGPL1 gene therapy. Our results additionally provide a new strategy (fasudil treatment) that could potentially be used alone or in combination with gene therapy to prevent kidney failure in SPLIS.