Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease

Mol Psychiatry. 2017 May;22(5):711-723. doi: 10.1038/mp.2016.148. Epub 2016 Sep 13.


Niemann-Pick disease type A (NPA) is a rare lysosomal storage disorder characterized by severe neurological alterations that leads to death in childhood. Loss-of-function mutations in the acid sphingomyelinase (ASM) gene cause NPA, and result in the accumulation of sphingomyelin (SM) in lysosomes and plasma membrane of neurons. Using ASM knockout (ASMko) mice as a NPA disease model, we investigated how high SM levels contribute to neural pathology in NPA. We found high levels of oxidative stress both in neurons from these mice and a NPA patient. Impaired activity of the plasma membrane calcium ATPase (PMCA) increases intracellular calcium. SM induces PMCA decreased activity, which causes oxidative stress. Incubating ASMko-cultured neurons in the histone deacetylase inhibitor, SAHA, restores PMCA activity and calcium homeostasis and, consequently, reduces the increased levels of oxidative stress. No recovery occurs when PMCA activity is pharmacologically impaired or genetically inhibited in vitro. Oral administration of SAHA prevents oxidative stress and neurodegeneration, and improves behavioral performance in ASMko mice. These results demonstrate a critical role for plasma membrane SM in neuronal calcium regulation. Thus, we identify changes in PMCA-triggered calcium homeostasis as an upstream mediator for NPA pathology. These findings can stimulate new approaches for pharmacological remediation in a disease with no current clinical treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Case-Control Studies
  • Cell Membrane / enzymology
  • Cell Membrane / metabolism
  • Child, Preschool
  • Disease Models, Animal
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurodegenerative Diseases / enzymology
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / enzymology
  • Neurons / metabolism
  • Niemann-Pick Disease, Type A / enzymology
  • Niemann-Pick Disease, Type A / metabolism*
  • Niemann-Pick Disease, Type A / pathology*
  • Oxidative Stress / physiology
  • Plasma Membrane Calcium-Transporting ATPases / antagonists & inhibitors*
  • Plasma Membrane Calcium-Transporting ATPases / metabolism
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingomyelins / metabolism*


  • Sphingomyelins
  • acid sphingomyelinase-1
  • Sphingomyelin Phosphodiesterase
  • Plasma Membrane Calcium-Transporting ATPases