Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease.
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.
Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
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Pérez-Cañamás
Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
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Benvegnù
Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigaciones Sanitarias, Fundación Jiménez Díaz, Madrid, Spain.
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Rueda
Fundación Centro de Investigación de Enfermedades Neurológicas (CIEN), Madrid, Spain.
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Rábano
Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigaciones Sanitarias, Fundación Jiménez Díaz, Madrid, Spain.
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Satrústegui
Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
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Ledesma
D000818:Animals; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D002675:Child, Preschool; D004195:Disease Models, Animal; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D052536:Niemann-Pick Disease, Type A / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism*
D013109:Sphingomyelins; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D053499:Plasma Membrane Calcium-Transporting ATPases