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Title: Pharmacological reversion of sphingomyelin-induced dendritic spine anomalies in a Niemann Pick disease type A mouse model
Authors: Arroyo, Ana I
Camoletto, Paola G
Morando, Laura
Sassoe-Pognetto, Marco
Giustetto, Maurizio
Van Veldhoven, Paul P
Schuchman, Edward H
Ledesma, Maria D # ×
Issue Date: Mar-2014
Publisher: Wiley-Blackwell Publishing Ltd.
Series Title: EMBO Molecular Medicine vol:6 pages:398-413
Abstract: 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.
URI: 
ISSN: 1757-4676
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Lipid Biochemistry and Protein Interactions
× corresponding author
# (joint) last author

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