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 (aSMaseS505A), 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. ASMaseS505A 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 aSMaseS505A mice. Together, these studies suggest a retention of L-SMase may serve to pave the way for ERT in NPD.