PLoS One：HDAC6与抑郁症相关

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.