Biosynthesis of N-acetylaspartate

描述(申请人提供)：N-乙酰天冬氨酸(NAA)是神经系统的一种丰富的(5-10 mM)氨基酸衍生物，临床上使用核磁共振波谱作为神经元功能完整性的非侵入性标记。降解酶天冬氨酸酶的先天性缺陷导致NAA降解减少导致Canavan病，这是一种常染色体隐性遗传性神经退行性疾病，在出生后发展，并导致10岁前死亡。其他研究表明，在包括精神分裂症在内的一些神经疾病中，特定神经系统中的NAA含量有所下降。最近的报道进一步强调了NAA在神经功能中的重要性，这些报告表明NAA与人类的认知能力和智力之间存在强烈的关联。这项提议的长期目标是确定NAA在神经元功能中的具体作用。中心假设是NAA是神经元线粒体谷氨酸氧化系统的组成部分。目前的目标是1)从大鼠脑线粒体中纯化生物合成酶天冬氨酸N-乙酰转移酶，2)产生抗体并通过免疫组织化学方法确定其细胞定位。为了达到这些目标，我们从大鼠脑线粒体中部分纯化了该酶，并将其表征为一种高分子量的酶复合体。这项拟议的研究将为后续研究奠定基础，以测试NAA是否调节一个或多个神经元功能，而不仅仅是作为神经元功能完整性的标志。这类研究应该有助于确定在精神分裂症等神经疾病中观察到的NAA减少是否在其发病机制中发挥作用。基于上述信息，旨在补充NAA的生化方法可能被开发为一种新的治疗策略。

DESCRIPTION (provided by applicant): N-Acetylaspartate (NAA) is an abundant (5-10 mM) amino acid derivative of the nervous system, which is used clinically as a noninvasive marker for the functional integrity of neurons using magnetic resonance spectroscopy. Decreased degradation of NAA resulting from a congenital defect in the degradative enzyme aspartoacylase causes Canavan disease, an autosomal-recessive neurodegenerative disorder that develops after birth and results in death before 10 years of age. Other studies have shown decreases in NAA in specific neuronal systems in a number of neurological disorders, including schizophrenia. Importance of NAA in neuronal functions has been further emphasized by recent reports that show a strong association between NAA and cognitive ability and intelligence in humans. The long-term goal of this proposal is to determine the specific roles of NAA in neuronal functions. The central hypothesis is that NAA is an integral component of the glutamate oxidation system in neuronal mitochondria. The immediate objectives are to 1) purify the biosynthetic enzyme aspartate N-acetyltransferase from rat brain mitochondria and 2) generate antibodies against the enzyme and determine its cellular localization by immunohistochemistry. Toward these objectives, we have partially purified the enzyme from rat brain mitochondria and characterized it as a high molecular weight enzyme complex. The proposed studies would set the foundation for subsequent studies to test whether or not NAA mediates one or more neuronal functions, instead of serving merely as a marker for the functional integrity of neurons. Such studies should help to determine whether or not the decreases in NAA observed in neurological diseases, such as schizophrenia, play a role in their pathogenesis. Based on the above information, biochemical approaches aimed at replenishing the NAA could be developed as a novel therapeutic strategy.