Original Article

Molecular Psychiatry (2017) 22, 711–723; doi:10.1038/mp.2016.148 published online 13 September 2016

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

A Pérez-Cañamás1, S Benvegnù1, C B Rueda1,2,3, A Rábano4, J Satrústegui1,2,3 and M D Ledesma1

  1. 1Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
  2. 2Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  3. 3Instituto de Investigaciones Sanitarias, Fundación Jiménez Díaz, Madrid, Spain
  4. 4Fundación Centro de Investigación de Enfermedades Neurológicas (CIEN), Madrid, Spain

Correspondence: Dr MD Ledesma, Centro Biología Molecular Severo Ochoa, Nicolás Cabrera 1, Madrid 28049, Spain. E-mail: dledesma@cbm.csic.es

Received 1 February 2016; Revised 28 June 2016; Accepted 13 July 2016
Advance online publication 13 September 2016

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Abstract

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.