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

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.

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

“…Compared to the control patient, Iba-1 immunostaining showed a substantial expansion of microglia in the cerebellum (Cb), cortex (Cx) and hippocampus (Hip) ( Fig 1A) in the NPA patient. In a previous study, we showed extensive neuronal death occurs in these brain areas (Perez-Canamas et al, 2017). Virtually all microglial cells in the NPA patient presented an amoeboid morphology with increased cell area ( Fig 1A-C), which is a characteristic feature of maximally activated microglia (Karperien et al, 2013).…”

“…Treatment with an inhibitor of glucosylceramide synthase that reduces ganglioside build-up (Zervas et al, 2001) stabilises neurological progression of NPC patients, but it does not cure the disease and has serious side effects. Lipid alterations in NPA and NPC diseases affect a number of biological processes including autophagy (Gabande-Rodriguez et al, 2014;Chung et al, 2016), synaptic function (Karten et al, 2006;Camoletto et al, 2009;Hawes et al, 2010;Arroyo et al, 2014) and calcium homeostasis (Lloyd-Evans et al, 2008;Perez-Canamas et al, 2017).…”

Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C

“…The calcium ATPase Pmc1 was previously shown in a genome-wide screen for protein-protein interactions to interact with Ncr1 (11), the confirmation of this interaction on the yeast vacuole is of particular interest as its mammalian orthologues, ATP2B1-4, are members of a family of plasma membrane ATPase (PMCA) calcium transporters (40). Interestingly, it has been demonstrated that sphingomyelin accumulation impairs PMCA activity, causing loss of calcium homeostasis, oxidative stress, and neurodegeneration (41). Storage of the same lipid occurs in NPC (39), as does loss of calcium homeostasis, oxidative stress, and neurodegeneration.…”

Contribution of Membrane Lipids to Postsynaptic Protein Organization

“…Despite synaptic receptors being integral membrane proteins that are embedded in the lipid bilayer, the contribution of lipids to synaptic organization and functioning remains poorly understood. Nevertheless, lipids are the most abundant components of the brain and lipid dysregulation is thought to underlie several cognitive disorders ( Kanungo et al, 2013 ; Martín et al, 2014 ; Pérez-Cañamás et al, 2017 ; van der Kant et al, 2019 ). Interestingly, synapses are enriched in specific lipid species such as cholesterol and sphingolipids ( Breckenridge et al, 1972 ) and other less abundant components, such as phosphoinositides.…”