19 mars 2017

Métabolisme phosphoinositide défectueux dans l'autisme

Aperçu : G.M.
Les phosphoinositides sont des composants essentiels des membranes lipidiques et des régulateurs cruciaux de nombreuses fonctions cellulaires, notamment la transduction du signal, le trafic des vésicules, la localisation et l'activité des récepteurs membranaires et la détermination de l'identité de la membrane. Les études génétiques et fonctionnelles montrent de plus en plus que ces enzymes sont souvent dysrégulées ou mutées dans les troubles du spectre de l'autisme. [...] cela offre des possibilités intéressantes d'explorer le métabolisme phosphoinositide altéré comme une cible thérapeutique chez les personnes avec certaines formes d'autisme. Cette revue résume les études génétiques et fonctionnelles qui identifient les défauts du métabolisme des phosphoinositides dans l'autisme et les troubles apparentés...

J Neurosci Res. 2017 May;95(5):1161-1173. doi: 10.1002/jnr.23797. Epub 2016 Jul 4.

Defective phosphoinositide metabolism in autism

Gross C1,2.

Author information

1
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
2
Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.

Abstract

Phosphoinositides are essential components of lipid membranes and crucial regulators of many cellular functions, including signal transduction, vesicle trafficking, membrane receptor localization and activity, and determination of membrane identity. These functions depend on the dynamic and highly regulated metabolism of phosphoinositides and require finely balanced activity of specific phosphoinositide kinases and phosphatases. There is increasing evidence from genetic and functional studies that these enzymes are often dysregulated or mutated in autism spectrum disorders; in particular, phosphoinositide 3-kinases and their regulatory subunits appear to be affected frequently. Examples of autism spectrum disorders with defective phosphoinositide metabolism are fragile X syndrome and autism disorders associated with mutations in the phosphoinositide 3-phosphatase tensin homolog deleted on chromosome 10 (PTEN), but recent genetic analyses also suggest that select nonsyndromic, idiopathic forms of autism may have altered activity of phosphoinositide kinases and phosphatases. Isoform-specific inhibitors for some of the phosphoinositide kinases have already been developed for cancer research and treatment, and a few are being evaluated for use in humans. Altogether, this offers exciting opportunities to explore altered phosphoinositide metabolism as a therapeutic target in individuals with certain forms of autism. This review summarizes genetic and functional studies identifying defects in phosphoinositide metabolism in autism and related disorders, describes published preclinical work targeting phosphoinositide 3-kinases in neurological diseases, and discusses the opportunities and challenges ahead to translate these findings from animal models and human cells into clinical application in humans. © 2016 Wiley Periodicals, Inc.
PMID: 27376697
PMCID: PMC5214992  [Available on 2017-11-01]
DOI: 10.1002/jnr.23797

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