Involvement of defective reversible-acetylation of non-histone proteins in mood disorders

我们以前的研究结果表明HDAC6介导的可逆乙酰化与情绪障碍有关。为了进一步研究和阐明HDAC6缺失如何引起情绪唤醒的分子机制，我们进行了行为测试，并在HDAC6敲除小鼠脑中寻找高乙酰化蛋白。HDAC6基因敲除小鼠表现出多动、焦虑减少和抗抑郁样行为。向野生型小鼠注射HDAC6特异性抑制剂也诱导抗抑郁样行为，表明HDAC6脱乙酰酶活性的丧失导致小鼠行为异常。在HDAC6基因敲除小鼠中，丙酮酸脱氢酶复合物在脑中被发现为高度乙酰化的蛋白质，并且在中缝核中丙酮酸增加。HDAC6与中缝核中的丙酮酸能神经元共定位，HDAC6的去乙酰化活性的丧失可能影响丙酮酸脱氢酶复合物的功能，导致丙酮酸能神经元的活性受到干扰，进而导致小鼠的情绪唤醒。

Our previous findings demonstrate that HDAC6-mediated reversible acetylation associates with the mood disorders. To further study and clarify the molecular mechanism how loss of HDAC6 causes emotional arousal, we performed behavioral tests and searched the hyper-acetylated protein(s) in HDAC6 knockout mouse brain. HDAC6 knockout mice showed hyperactivity, less-anxiety, and antidepressant-like behavior. Injection of specific inhibitor of HDAC6 to wild-type mice also induced antidepressant-like behavior, indicating that loss of deacetylase activity of HDAC6 causes abnormal behavior in mice. In HDAC6 knockout mice, the pyruvate dehydrogenase complex was found as a hyper-acetylated protein in brain, and the pyruvate increased in raphe nuclei. Taken together the findings that HDAC6 is well co-localized to serotonergic neurons in raphe nuclei, loss of deacetylate activity of HDAC6 might affect the function of pyruvate dehydrogenase complex, leading to disturb the activity of serotonergic neurons, which in turn, result in emotional arousal in mice.