Rotermund Carola, Reolon Gustavo K, Leixner Sarah, Boden Cindy, Bilbao Ainhoa, Kahle Philipp J
Laboratory of Functional Neurogenetics, Department of Neurodegeneration, German Center of Neurodegenerative Diseases, Tübingen, Germany.
Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
J Neurochem. 2017 Nov;143(3):294-305. doi: 10.1111/jnc.14151. Epub 2017 Sep 12.
α-Synuclein (αSYN) is the neuropathological hallmark protein of Parkinson's disease (PD) and related neurodegenerative disorders. Moreover, the gene encoding αSYN (SNCA) is a major genetic contributor to PD. Interestingly, independent genome-wide association studies also identified SNCA as the most important candidate gene for alcoholism. Furthermore, single-nucleotide-polymorphisms have been associated with alcohol-craving behavior and alcohol-craving patients showed augmented αSYN expression in blood. To investigate the effect of αSYN on the addictive properties of chronic alcohol use, we examined consumption, motivation, and seeking responses induced by environmental stimuli and relapse behavior in transgenic mice expressing the human mutant [A30P]αSYN throughout the brain. The primary reinforcing effects of alcohol under operant self-administration conditions were increased, while consumption and the alcohol deprivation effect were not altered in the transgenic mice. The same mice were subjected to immunohistochemical measurements of immediate-early gene inductions in brain regions involved in addiction-related behaviors. Acute ethanol injection enhanced immunostaining for the phosphorylated form of cAMP response element binding protein in both amygdala and nucleus accumbens of αSYN transgenic mice, while in wild-type mice no effect was visible. However, at the same time, levels of cFos remain unchanged in both genotypes. These results provide experimental confirmation of SNCA as a candidate gene for alcoholism in addition to its known link to PD.
α-突触核蛋白（αSYN）是帕金森病（PD）及相关神经退行性疾病的神经病理学标志性蛋白。此外，编码αSYN的基因（SNCA）是PD的主要遗传因素。有趣的是，独立的全基因组关联研究也将SNCA确定为酒精中毒最重要的候选基因。此外，单核苷酸多态性与酒精渴望行为有关，且有酒精渴望的患者血液中αSYN表达增加。为了研究αSYN对慢性酒精使用成瘾特性的影响，我们检测了在全脑表达人类突变型[A30P]αSYN的转基因小鼠中，环境刺激诱导的饮酒量、动机和寻求反应以及复发行为。在操作性自我给药条件下，酒精的主要强化作用增强，而转基因小鼠的饮酒量和酒精剥夺效应未改变。对相同的小鼠进行了与成瘾相关行为的脑区即刻早期基因诱导的免疫组织化学测量。急性乙醇注射增强了αSYN转基因小鼠杏仁核和伏隔核中cAMP反应元件结合蛋白磷酸化形式的免疫染色，而野生型小鼠中未观察到影响。然而，同时，两种基因型的cFos水平均保持不变。这些结果为SNCA作为除已知与PD相关之外的酒精中毒候选基因提供了实验证据。
