title: Improvement of biochemical and behavioral defects in the Niemann-Pick type A mouse by intraventricular infusion of MARCKS.
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.
authors.affiliation: Center for Human Genetics, VIB Center for the Biology of Disease and Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Laura.Trovo@lrz.tu-muenchen.de.
authors.forename: Laura
authors.initials: L
authors.lastname: Trovò
authors.affiliation: Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven (K.U. Leuven), Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven (K.U. Leuven), Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Centro Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Ledesma
authors.affiliation: Centro Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain. Electronic address: cdotti@cbm.csic.es.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000627:therapeutic use*; D001523:Mental Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D053580:Muscle Strength / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D052536:Niemann-Pick Disease, Type A / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051966:Phospholipase C gamma / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D051966:Phospholipase C gamma
keywords: ASMko mice; Behavior; MARCKS; PI(4,5)P2