Al-Housseini Ali M, Sivanandam Thamil Mani, Bradbury Edward L, Tannenberg Rudi K, Dodd Peter R, Gu Qiang
Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Alcohol Clin Exp Res. 2008 Jun;32(6):1080-90. doi: 10.1111/j.1530-0277.2008.00670.x. Epub 2008 Apr 26.
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 alpha-, beta-, and delta-catenins, their upstream activators cadherin-3 (type I cadherin) and cadherin-5 (type II cadherin), and 5 cytoplasmic regulators c-Src, CK1 epsilon, GSK-3beta, PP2A-C alpha, and APC, as well as the nuclear complex partner of beta-catenin CBP and 2 downstream genes Myc and cyclin D1. ILK, G(alpha1), G(beta1), and G(beta2), which are activity regulators of GSK-3beta, were also analyzed.
Both alpha- and beta-catenin showed significantly increased levels, while delta-catenin did not change significantly, in chronic alcoholics. In addition, the level of the beta-catenin downstream gene product Myc was significantly increased. Average levels of the catenin regulators c-Src, CK1 epsilon, 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 alpha- and beta-catenin levels, which in turn increase downstream gene expressions such as Myc that is controlled by beta-catenin signaling. This study showed that the beta-catenin signal transduction pathway was upregulated by chronic alcohol abuse, and prompts further investigation of mechanisms underlying the upregulation of alpha- and beta-catenins in alcoholism, which may have considerable pathogenic and therapeutic relevance.
长期大量酗酒会导致大脑发生神经适应性变化。与酒精中毒相关的行为、心理、情感和神经病理学特征的复杂性，可能反映了特定脑区中受酒精诱导基因表达模式影响的蛋白质网络。然而，在分子水平上，关于长期酗酒对蛋白质表达水平改变的了解仍然有限。因此，能够全面评估这种复杂性的新技术，将有助于同时评估相关神经回路中一组蛋白质的变化。
采用抗体微阵列进行蛋白质组学分析，以确定慢性酒精中毒患者与年龄和性别匹配的对照受试者额叶上皮质中蛋白质水平的差异。分析了17种与连环蛋白信号通路相关的蛋白质，包括α -、β - 和δ - 连环蛋白，它们的上游激活因子钙黏蛋白 - 3（I型钙黏蛋白）和钙黏蛋白 - 5（II型钙黏蛋白），以及5种细胞质调节因子c - Src、CK1ε、GSK - 3β、PP2A - Cα和APC，还有β - 连环蛋白的核复合物伙伴CBP以及2个下游基因Myc和细胞周期蛋白D1。还分析了作为GSK - 3β活性调节因子的ILK、G(α1)、G(β1)和G(β2)。
慢性酒精中毒患者中，α - 连环蛋白和β - 连环蛋白水平均显著升高，而δ - 连环蛋白无显著变化。此外，β - 连环蛋白下游基因产物Myc的水平显著升高。慢性酒精中毒患者中连环蛋白调节因子c - Src、CK1ε和APC的平均水平也有所升高，但变化无统计学意义。
长期大量饮酒导致α - 和β - 连环蛋白水平上调，进而增加下游基因如受β - 连环蛋白信号控制的Myc的表达。本研究表明慢性酗酒会上调β - 连环蛋白信号转导通路，并促使进一步研究酒精中毒中α - 和β - 连环蛋白上调的潜在机制，这可能具有重要的致病和治疗意义。
