A zebrafish model of Combined Saposin Deficiency identifies acid sphingomyelinase as a potential therapeutic target.

Sphingolipidoses are a subcategory of lysosomal storage diseases (LSDs) caused by mutations in enzymes of the sphingolipid catabolic pathway. Like many LSDs, neurological involvement in sphingolipidoses leads to early mortality with limited treatment options. Given the role of myelin loss as a major contributor toward LSD-associated neurodegeneration, we investigated the pathways contributing to demyelination in a CRISPR-Cas9 zebrafish model of Combined Saposin Deficiency (psap). psap zebrafish recapitulated major LSD pathologies including reduced lifespan, lipid storage, impaired locomotion, and severe myelin loss; loss of myelin basic protein a (mbpa) mRNA was progressive with no changes in additional markers of oligodendrocyte differentiation. Brain transcriptomics revealed dysregulated mTORC1 signaling and elevated neuroinflammation, where increased proinflammatory cytokine expression preceded and mTORC1 signaling changes followed mbpa loss. We examined pharmacological and genetic rescue strategies via 1) water tank administration of the multiple sclerosis drug monomethylfumarate (MMF), and 2) crossing the psap line into an acid sphingomyelinase deficiency (smpd1) model.1,2 Smpd1 mutagenesis, but not MMF, prolonged lifespan in psap zebrafish, highlighting the modulation of acid sphingomyelinase activity as a potential path toward sphingolipidosis treatment.