Nitta Atsumi, Noike Hiroshi, Sumi Kazuyuki, Miyanishi Hajime, Tanaka Takuya, Takaoka Kazuya, Nagakura Miyuki, Iegaki Noriyuki, Kaji Jin-ichiro, Miyamoto Yoshiaki, Muramatsu Shin-Ichi, Uno Kyosuke
Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan
Shati/Nat8l was originally isolated as a methamphetamine-related-molecule from the nucleus accumbens of mice. Since then, Shati/Nat8l has been characterized as an -acetyltransferase-8-like protein (Nat8l) that catalyzes -acetylaspartate (NAA) synthesis from aspartate and acetyl-coenzyme A. It has been shown that elevated NAA levels detected by proton magnetic resonance spectroscopy (H-MRS) brain imaging indicates increased neuronal activity. Our group produced Shati/Nat8l knock out mice (Shati/Nat8l KO mice), which exhibit hyper locomotion, anxiety behaviors, and social dysfunction. These mice have a high sensitivity to methamphetamine, as evidenced by their results in assessments of locomotor activity and conditioned place preference, as well as their elevated dopamine levels. We used an adeno-associated virus (AAV) vector containing (AAV-) to overexpress the protein in different brain regions such as the striatum and the nucleus accumbens, in order to investigate their involvement in methamphetamine-induced behavioral and pharmacological changes. We showed that overexpression of accumbal Shati/Nat8l attenuates methamphetamine-induced behaviors. Recent clinical studies have revealed further novel roles of Shati/Nat8l in psychiatric and neuronal diseases. We are just beginning to appreciate the various actions of this intriguing, recently discovered molecule in the central nervous system.
Shati/Nat8l最初是从小鼠伏隔核中作为一种与甲基苯丙胺相关的分子分离出来的。从那时起，Shati/Nat8l被鉴定为一种类似乙酰转移酶-8的蛋白质（Nat8l），它催化由天冬氨酸和乙酰辅酶A合成N-乙酰天冬氨酸（NAA）。质子磁共振波谱（H-MRS）脑成像检测到的NAA水平升高表明神经元活动增加。我们的团队培育出了Shati/Nat8l基因敲除小鼠（Shati/Nat8l KO小鼠），这些小鼠表现出过度活动、焦虑行为和社交功能障碍。这些小鼠对甲基苯丙胺高度敏感，这在它们的运动活动评估、条件性位置偏爱实验结果以及多巴胺水平升高中得到了证实。我们使用携带（AAV-）的腺相关病毒（AAV）载体在纹状体和伏隔核等不同脑区过表达该蛋白质，以研究它们在甲基苯丙胺诱导的行为和药理学变化中的作用。我们发现伏隔核Shati/Nat8l的过表达减弱了甲基苯丙胺诱导的行为。最近的临床研究揭示了Shati/Nat8l在精神疾病和神经疾病中的更多新作用。我们才刚刚开始认识到这种有趣的、最近发现的分子在中枢神经系统中的各种作用。
