Retention of lysosomal acid sphingomyelinase protects from Niemann-Pick Disease

Niemann-Pick Disease (NPD) types A and B are lysosomal storage disorders resulting from dysfunction or loss of acid sphingomyelinase (aSMase), which hydrolyzes sphingomyelin (SM) to ceramide and phosphocholine. Patients with NPD-A develop severe neurologic and visceral pathology and rarely live beyond the age of 3 years, while patients with NPD-B typically live to adolescence/early adulthood without neurologic involvement. There are currently no therapies for NPD-A. SMPD1, the gene that encodes aSMase, gives rise to two distinct enzymes - lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase), with the latter being associated with inflammation and chemokine amplification. This study sought to define the role of secretory-deficient aSMase variants in NPD. Human NPD fibroblasts transfected with wildtype or two aSMase variants demonstrated that serine residues at either position 507 or 508 in human aSMase retained L-SMase yet lacked S-SMase activity, basally and in response to inflammatory stimuli. We next generated a novel mouse model harboring the S505A variant (aSMase^S505A), corresponding to S507A in humans, in the endogenous Smpd1 gene. Mice expressing the S505A variant of aSMase retained L-SMase activity and tissue SM levels in the brain but lacked S-SMase activity in serum. ASMase^S505A mice were protected from NPD physiology and pathophysiology including accumulation of foam cells in the spleen, liver and cerebellum, as well as loss of Purkinje cells. Moreover, aSMase^-/- mice demonstrated significantly decreased locomotor control and this was prevented in aSMase^S505A mice. Together, these studies suggest a retention of L-SMase may serve to pave the way for ERT in NPD.