Pharmacological reversion of sphingomyelin‐induced dendritic spine anomalies in a Niemann Pick disease type A mouse model

Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. W...

Full description

Saved in:

Bibliographic Details
Published in:	EMBO molecular medicine Vol. 6; no. 3; pp. 398 - 413
Main Authors:	Arroyo, Ana I, Camoletto, Paola G, Morando, Laura, Sassoe‐Pognetto, Marco, Giustetto, Maurizio, Van Veldhoven, Paul P, Schuchman, Edward H, Ledesma, Maria D
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-03-2014 John Wiley & Sons, Inc EMBO Press Blackwell Publishing Ltd Springer Nature
Subjects:	Actin Actin Cytoskeleton - drug effects Animals Apoptosis - drug effects Brain Brain diseases Cells, Cultured Cholesterol Cognitive ability Cytoskeleton Dendritic spines Dendritic Spines - drug effects Dendritic Spines - metabolism dexamethasone Dexamethasone - pharmacology Disease Disease Models, Animal EMBO16 EMBO27 Female Genetic disorders Glutamate Glutamate receptors Glutamic acid receptors (metabotropic) Grants Kinases Lipids Membranes Memory, Short-Term - drug effects Metabolic disorders Metabolism Mice Mice, Inbred C57BL Mice, Knockout Microscopy Molecular modelling Motor Activity - drug effects Muscle proteins Mutation Neurons Neurons - cytology Neurons - drug effects Neurons - metabolism Niemann Pick Niemann-Pick disease Niemann-Pick Disease, Type A - drug therapy Niemann-Pick Disease, Type A - metabolism Niemann-Pick Disease, Type A - pathology Phenotypes Phospholipids Physiological aspects Pick's disease Polymerization Proteins Research Article Reversion RhoA RhoA protein Sphingomyelin Sphingomyelin phosphodiesterase Sphingomyelin Phosphodiesterase - deficiency Sphingomyelin Phosphodiesterase - genetics Sphingomyelin Phosphodiesterase - metabolism Sphingomyelins - toxicity Steroids Therapeutic applications dexamethasone sphingomyelin Niemann Pick RhoA
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions. Synopsis A novel pathway is described in a Niemann Pick mouse model whereby elevated sphingomyelin impairs dendritic spines by modulating the actin cytoskeleton. Pharmacological activation of sphingomyelin catabolism in vivo with dexamethasone ameliorates the pathology of affected mice. Sphingomyelin accumulation leads to dendritic spine anomalies in mice lacking acid sphingomyelinase, which are a model for Niemann Pick disease type A. Sphingomyelin levels impact dendritic spine actin cytoskeleton through the modulation of the RhoA‐ROCK‐Profillin IIa pathway. Activation of neutral sphingomyelinase (NSM) reduces sphingomyelin and restores filamentous actin levels in synapses lacking acid sphingomyelinase. Oral administration of dexamethasone, an NSM activator, prevents synaptic anomalies, neuronal death and functional deficits in mice lacking acid sphingomyelinase. Graphical Abstract A novel pathway is described in a Niemann Pick mouse model whereby elevated sphingomyelin impairs dendritic spines by modulating the actin cytoskeleton. Pharmacological activation of sphingomyelin catabolism in vivo with dexamethasone ameliorates the pathology of affected mice.
Bibliography:	These authors contributed equally to this work.
ISSN:	1757-4676 1757-4684
DOI:	10.1002/emmm.201302649