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

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.
AuthorsAna I Arroyo, Paola G Camoletto, Laura Morando, Marco Sassoe-Pognetto, Maurizio Giustetto, Paul P Van Veldhoven, Edward H Schuchman, Maria D Ledesma
JournalEMBO molecular medicine (EMBO Mol Med) Vol. 6 Issue 3 Pg. 398-413 (03 2014) ISSN: 1757-4684 [Electronic] England
PMID24448491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Sphingomyelins
  • Dexamethasone
  • Sphingomyelin Phosphodiesterase
Topics
  • Actin Cytoskeleton (drug effects)
  • Animals
  • Apoptosis (drug effects)
  • Cells, Cultured
  • Dendritic Spines (drug effects, metabolism)
  • Dexamethasone (pharmacology)
  • Disease Models, Animal
  • Female
  • Memory, Short-Term (drug effects)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity (drug effects)
  • Neurons (cytology, drug effects, metabolism)
  • Niemann-Pick Disease, Type A (drug therapy, metabolism, pathology)
  • Sphingomyelin Phosphodiesterase (deficiency, genetics, metabolism)
  • Sphingomyelins (toxicity)

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