Biosynthesis of N-acetylaspartate

描述（由申请人提供）：N-乙酰天冬氨酸（NAA）是神经系统的丰富（5-10 mM）氨基酸衍生物，其在临床上用作使用磁共振波谱分析的神经元功能完整性的非侵入性标记物。由于降解酶天冬氨酸酰化酶的先天性缺陷而导致的NAA降解减少会导致卡纳万病，这是一种常染色体隐性神经退行性疾病，在出生后发生，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系统疾病中，特定神经元系统的NAA减少。NAA在神经元功能中的重要性已被最近的报告进一步强调，这些报告显示NAA与人类的认知能力和智力之间存在强烈的关联。该提案的长期目标是确定NAA在神经元功能中的具体作用。中心假设是NAA是神经元线粒体中谷氨酸氧化系统的组成部分。直接目标是：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）产生针对该酶的抗体，并通过免疫组织化学确定其细胞定位。为了实现这些目标，我们已经部分纯化的酶从大鼠脑线粒体，其特征在于它作为一个高分子量的酶复合物。这些研究将为后续研究奠定基础，以测试NAA是否介导一种或多种神经元功能，而不仅仅是作为神经元功能完整性的标志。这些研究应该有助于确定在神经系统疾病（如精神分裂症）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的生物化学方法可以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.