Abstract
Niemann-Pick disease type A (NPDA) is a fatal disease due to mutations in the acid sphingomyelinase (ASM) gene, which triggers the abnormal accumulation of sphingomyelin (SM) in lysosomes and the plasma membrane of mutant cells. Although the disease affects multiple organs, the impact on the brain is the most invalidating feature. The mechanisms responsible for the cognitive deficit characteristic of this condition are only partially understood. Using mice lacking the ASM gene (ASMko), a model system in NPDA research, we report here that high sphingomyelin levels in mutant neurons lead to low synaptic levels of phosphoinositide PI(4,5)P2 and reduced activity of its hydrolyzing phosphatase PLCγ, which are key players in synaptic plasticity events. In addition, mutant neurons have reduced levels of membrane-bound MARCKS, a protein required for PI(4,5)P2 membrane clustering and hydrolysis. Intracerebroventricular infusion of a peptide that mimics the effector domain of MARCKS increases the content of PI(4,5)P2 in the synaptic membrane and ameliorates behavioral abnormalities in ASMko mice.
Keywords:
ASMko mice; Behavior; MARCKS; PI(4,5)P2.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Avoidance Learning / drug effects
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Brain / drug effects
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Brain / metabolism*
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Brain / pathology
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Disease Models, Animal
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Exploratory Behavior / drug effects
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Injections, Intraventricular
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Intracellular Signaling Peptides and Proteins / therapeutic use*
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Lipid Metabolism / drug effects
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Lipid Metabolism / genetics
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Membrane Proteins / therapeutic use*
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Mental Disorders / drug therapy*
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Mental Disorders / etiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / genetics
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Muscle Strength / drug effects
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Muscle Strength / genetics
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Mutation / genetics
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Myristoylated Alanine-Rich C Kinase Substrate
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Niemann-Pick Disease, Type A / complications*
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Niemann-Pick Disease, Type A / drug therapy*
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Niemann-Pick Disease, Type A / metabolism
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Niemann-Pick Disease, Type A / pathology
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Phospholipase C gamma / metabolism
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Sphingomyelin Phosphodiesterase / genetics
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Synaptosomes / drug effects
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Synaptosomes / metabolism
Substances
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Intracellular Signaling Peptides and Proteins
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Marcks protein, mouse
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Membrane Proteins
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Myristoylated Alanine-Rich C Kinase Substrate
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acid sphingomyelinase-1
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Sphingomyelin Phosphodiesterase
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Phospholipase C gamma