DHHC 15 palmitoylation modulates striatal dopamine system

描述(申请人提供)：注意缺陷多动障碍(ADHD)是一种常见的精神障碍，在全球学龄儿童和成人中的患病率分别为3%-7%和4%。精神冲剂被广泛用于ADHD症状的治疗，疗效良好。然而，临床疗效多变，对标准治疗方案无反应和耐受性，以及在以后的生活中滥用药物和精神疾病的风险增加，仍然是令人严重关切的问题。人类和动物模型的临床、遗传学和脑成像研究以及精神刺激剂的临床疗效广泛支持ADHD患者纹状体多巴胺(DA)系统的异常调节。尽管经过几十年的研究，但ADHD的确切神经生物学机制仍然知之甚少，这严重阻碍了新的、安全和有效的治疗方法的开发。棕榈酰化是由DHHC结构域的棕榈酰基转移酶家族催化的可逆的脂类翻译后修饰。我们已经产生了一系列DHHC15基因敲除的小鼠，这些小鼠表现出多动和纹状体DA水平降低。突变小鼠的过度活动对苯丙胺、DAT抑制剂和DA受体反向激动剂有反应，提示纹状体DA系统的特异性参与。我们推测，这些与ADHD相关的表型是由纹状体中一个或多个DHHC15底物的棕榈酰化缺陷引起的。在这项研究中，我们建议使用功能分析和蛋白质组学方法在纹状体中鉴定dhc15的活体底物，并表征其潜在的神经生物学机制。研究结果将为纹状体多巴胺的一种新的调节机制提供有价值的见解，并有助于为合理开发有效的治疗ADHD的药物靶点提供帮助。

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder with a prevalence of 3- 7% in school-aged children and 4% in adults worldwide. Psychostamulants are extensively used for treatment of ADHD symptoms with a favorable response. However, variable clinical effectiveness, non- responsiveness and tolerance to standard treatment regimens, and increasing risks for drug abuse and mental illnesses later in life continue to be serious concerns. Dysregulations of striatal dopamine (DA) system in ADHD are widely supported by clinical, genetic, and brain imaging studies in humans and animal models, and by clinical effectiveness of psychostimulants. Despite decades of research, the precise neurobiological mechanisms for ADHD remain poorly understood, which severely hampers the development of novel, safe, and effective therapies. Palmitoylation is a reversible lipid post-translational modification catalyzed by a family of DHHC-domain palmitoyltransferases. We have generated a line of DHHC15-knockout mice that show hyperactivity and reduced DA levels in striatum. Hyperactivity in the mutant mice is responsive to amphetamine, DAT inhibitor and DA receptor inverse agonist suggesting a specific involvement of striatal DA system. We hypothesize that these ADHD-related phenotype are caused by defects in palmitoylation of one or more DHHC15 substrates in striatum. In this study, we propose to identify dhhc15 in vivo substrates in striatum using functional assays and proteomics, and to characterize the underlying neurobiological mechanisms. Results shall provide valuable insights into a novel regulatory mechanism of DA in striatum and help to identify drug targets for rational development of effective therapies for ADHD.