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PLoS One:HDAC6与抑郁症相关

作者:MedSci 来源:MedSci 日期:2022-01-12
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         日本研究人员发现脑部神经细胞内含量很高的一种蛋白质与抑郁症有关。

关键字:  抑郁症 |  | HDAC6 

        日本研究人员发现脑部神经细胞内含量很高的一种蛋白质与抑郁症有关。如果阻碍这种蛋白质发挥作用,能获得与使用抗抑郁药物相同的效果。相关报告已刊登在美国科学杂志《科学公共图书馆—综合》PLoS One的网络版上。

        日本爱知县身心障碍者精神发育障碍研究所与名古屋市立大学研究人员发现,在大脑发育时,一种名为HDAC6的蛋白质会增多。而在产生血清素的神经细胞中,也含有很多这种蛋白质。血清素对调节不安等情绪发挥着重要作用。

        研究人员让体内不含HDAC6蛋白质的小鼠与普通小鼠一起运动,结果发现,与普通小鼠相比,没有这种蛋白质的小鼠能多运动1分钟。懒于运动是抑郁症的症状之一。此外,没有这种蛋白质的小鼠在新环境中也显得更活跃,在很高的地点不会感到不安。

        研究人员随后给一些普通小鼠服用了阻碍这种蛋白质发挥作用的药物。结果发现,小鼠在服用这种药物后,运动时间比正常情况下延长1分钟。这表明,如果阻碍这种蛋白质发挥作用,能获得与使用抗抑郁药物相同的效果。

        研究人员川口祯晴指出,这一发现有望帮助弄清抑郁症的病理和开发出新的抗抑郁药物。

        doi:10.1371/journal.pone.0030924

        Loss of Deacetylation Activity of Hdac6 Affects Emotional Behavior in Mice

        Masahide Fukada1, Atsuko Hanai1, Atsuo Nakayama1, Takayoshi Suzuki2, Naoki Miyata2, Ramona M. Rodriguiz3, William C. Wetsel3, Tso-Pang Yao4, Yoshiharu Kawaguchi1*

        Acetylation of the ε-amino group of lysine is a reversible post-translational modification mediated by acetyltransferases and deacetylases. This type of acetylation is not restricted to histones but also occurs on diverse proteins and affects functions such as DNA binding, protein-protein interaction, enzymatic activity, and stability. Therefore, lysine acetylation emerges as an important post-translational modification that regulates a wide range of cellular processes (reviewed in [1]). Histone deacetylases (HDACs) are a family of enzymes with 18 isoforms in mammals, and are grouped into four classes by sequence homology [2]. HDAC6 belongs to class II, and has a unique structure with two catalytic domains and a C-terminal BUZ domain that binds ubiquitin. HDAC6 gene is located on X chromosome both in mice and human genome [3], [4]. In mice, Hdac6 protein is broadly expressed in multiple tissues, particularly abundant in the brain and testis (Fig. S1) [5]. HDAC6 is known to be a multi-functional cytoplasmic deacetylase that controls cell motility [6]–[9], endocytosis [10], vesicle transport [11], glucocorticoid receptor maturation [12], autophagic protein degradation [13]–[15], and aggresome formation [16] by deacetylating α-tubulin, cortactin, and Hsp90. These cellular events are closely related to the acquisition and maintenance of proper function in neurons. For example, at synapses, vesicle transport and endocytosis are underlying mechanisms for neurotransmitter release and recycling. Glucocorticoid receptor maturation is necessary for the negative feedback regulation of stress at the hippocampus [17]. Autophagic protein degradation and aggresome formation are a part of the quality control of proteins, and their disturbance leads to neurodegenerative disorders [18]. Despite the fact that Hdac6 protein is abundantly expressed in mice brain, the physiological implications of Hdac6 as well as non-histone acetylation in neural function are poorly understood. In this study, we found that Hdac6 is highly expressed in serotonergic neuron, and that loss of Hdac6 deacetylase activity leads to hyperactivity, less-anxiety and antidepressant-like behavior in mice. Our findings suggest that Hdac6-mediated non-histone deacetylation plays crucial roles in the expression of emotional behaviors.

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