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Monday, May 5, 2008

Upregulation of β-Catenin Levels in Superior Frontal Cortex of Chronic Alcoholics
Alcoholism: Clinical and Experimental Research OnlineEarly Articles 28 Apr 2008

Chronic and excessive alcohol misuse results in neuroadaptive changes in the brain. The complex nature of behavioral, psychological, emotional, and neuropathological characteristics associated with alcoholism is likely a reflection of the network of proteins that are affected by alcohol-induced gene expression patterns in specific brain regions. At the molecular level, however, knowledge remains limited regarding alterations in protein expression levels affected by chronic alcohol abuse. Thus, novel techniques that allow a comprehensive assessment of this complexity will enable the simultaneous assessment of changes across a group of proteins in the relevant neural circuitry.

A proteomics analysis was performed using antibody microarrays to determine differential protein levels in superior frontal cortices between chronic alcoholics and age- and gender-matched control subjects. Seventeen proteins related to the catenin signaling pathway were analyzed, including α-, β-, and δ-catenins, their upstream activators cadherin-3 (type I cadherin) and cadherin-5 (type II cadherin), and 5 cytoplasmic regulators c-Src, CK1ε, GSK-3β, PP2A-Cα, and APC, as well as the nuclear complex partner of β-catenin CBP and 2 downstream genes Myc and cyclin D1. ILK, Gα1, Gβ1, and Gβ2, which are activity regulators of GSK-3β, were also analyzed.

Both α- and β-catenin showed significantly increased levels, while δ-catenin did not change significantly, in chronic alcoholics. In addition, the level of the β-catenin downstream gene product Myc was significantly increased. Average levels of the catenin regulators c-Src, CK1ε, and APC were also increased in chronic alcoholics, but the changes were not statistically significant.

Chronic and excessive alcohol consumption leads to an upregulation of α- and β-catenin levels, which in turn increase downstream gene expressions such as Myc that is controlled by β-catenin signaling. This study showed that the β-catenin signal transduction pathway was upregulated by chronic alcohol abuse, and prompts further investigation of mechanisms underlying the upregulation of α- and β-catenins in alcoholism, which may have considerable pathogenic and therapeutic relevance.

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