Science : Schizophrénie et génétique


De plus en plus d'indices tendent à impliquer une origine génétique à la schizophrénie.
Cette semaine dans le très relevé Journal of Clinical Investigation (JCI), un article et un éditorial sur le lien entre la protéine de signalisation AKT1 et la schizophrénie.

Ouvrant des perspectives aussi bien dans la compréhension de l'origine de cette maladie qu'à de futurs approches thérapeutiques.

L'abstract de l'article

J Clin Invest. 2008 May 22.
Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans.

Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR.

Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, NIH, Bethesda, Maryland, USA.

AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.

L'abstract de l'éditorial

J Clin Invest. 2008 May 22.

A signaling pathway AKTing up in schizophrenia.

Arguello PA, Gogos JA.

Department of Neuroscience and Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA.

The serine/threonine protein kinase AKT (also known as PKB) signaling pathway has been associated with several human diseases, including schizophrenia. Studies in preclinical models have demonstrated that impaired AKT signaling affects neuronal connectivity and neuromodulation and have identified AKT as a key signaling intermediary downstream of dopamine (DA) receptor 2 (DRD2), the best-established target of antipsychotic drugs. A study by Tan et al. in this issue of the JCI strengthens links among AKT signaling, DA transmission, and cognition in healthy individuals and offers potential avenues to explore in an effort to find more effective pharmacotherapies for schizophrenia and related disorders

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