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

Molecular Psychiatry volume 22, pages 711–723 (2017)Cite this article

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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.

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Acknowledgements

We thank the Wylder Nation Foundation for kindly donating the NPA brain tissue, EH Schuchman (Mount Sinai School of Medicine, New York) for providing us with the ASMko mice, AM Mata (Universidad de Extremadura) and JJ Lucas (CBMSO) for technical advice, and C. Aragón, B. López-Corcuera and E. Núñez for providing the Caloxin 2a1 and for their advice on its use. This work was financed by grants from the Ministerio Español de Ciencia e Innovación (SAF2014-57539- R and CSD2010-00045) and the Fundación Niemann Pick España to MDL, and by an institutional grant to the CBMSO from the Fundación Ramón Areces. APC holds a predoctoral fellowship (FPU) funded by the Ministerio Español de Ciencia e Innovación. We thank Life Science Editors for editing services.

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  1. Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain

    A Pérez-Cañamás, S Benvegnù, C B Rueda, J Satrústegui & M D Ledesma

  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    C B Rueda & J Satrústegui

  3. Instituto de Investigaciones Sanitarias, Fundación Jiménez Díaz, Madrid, Spain

    C B Rueda & J Satrústegui

  4. Fundación Centro de Investigación de Enfermedades Neurológicas (CIEN), Madrid, Spain

    A Rábano

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Pérez-Cañamás, A., Benvegnù, S., Rueda, C. et al. Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann–Pick disease. Mol Psychiatry 22, 711–723 (2017). https://doi.org/10.1038/mp.2016.148

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