Document Type
Article
Publication Date
11-1-2025
Original Citation
Beard C,
Hermanson K,
Snider J,
Hara A,
Dahl B,
Allopenna J,
Marron M,
Newcomb B,
Low BE,
Wiles MV,
Jenkins R,
Obeid L,
Hannun Y,
Snider A.
Retention of lysosomal acid sphingomyelinase protects from Niemann-Pick Disease. Neurobiol Dis. 2025;216:107147.
Keywords
JMG, Sphingomyelin Phosphodiesterase, Animals, Humans, Niemann-Pick Diseases, Mice, Lysosomes, Mice, Knockout, Male, Mice, Inbred C57BL, Disease Models, Animal, Fibroblasts, Niemann-Pick Disease, Type A
JAX Source
Neurobiol Dis. 2025;216:107147.
ISSN
1095-953X
PMID
41106691
DOI
https://doi.org/10.1016/j.nbd.2025.107147
Abstract
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
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This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 International License.