Canavan Disease: Pathogenesis and Treatment

Canavan病（CD）是一种常染色体隐性神经退行性疾病，由编码天冬氨酸酰化酶（ASPA）的基因突变引起。ASPA催化n -乙酰天冬氨酸（NAA）的去乙酰化，NAA是一种丰富的（~ 10 mM）神经系统特异性氨基酸衍生物。CD的特点是大脑海绵状变性，导致严重的精神运动迟缓，大多数患儿在10岁前死亡。乳糜泻的确切发病机制尚不清楚。核心假设是，髓磷脂合成需要ASPA活性，通过释放naa衍生的醋酸酯来合成乙酰辅酶a，乙酰辅酶a用于髓磷脂脂质部分的合成。在这个假设中，CD被认为是由NAA衍生的醋酸盐供应不足引起的髓磷脂合成缺陷引起的。许多研究，包括我们最近证明的ASPA在中枢神经系统少突胶质细胞中的选择性定位，都与CD的醋酸盐缺乏假说一致。此外，我们最近通过1)测定脑中的醋酸盐水平和2)研究髓磷脂相关脂质合成，直接在小鼠CD模型（ASPA -/-）中验证了醋酸盐缺乏假说。结果表明，CD小鼠脑内醋酸盐水平下降约80%，一些髓磷脂相关脂质的合成也显著减少。这些结果为支持这一假设提供了第一个直接证据。这些发现的主要含义是,醋酸补充可能会提供一个简单和廉价的治疗方法CD。为了实现这个目标,我们取得了进展,发现口服三乙酸甘油酯(三醋精),乙酸前体,导致大脑中醋酸含量增加约10倍在1 - 2小时,醋酸和努力来测试是否补充使用三乙酸甘油酯是有效的治疗CD正在进行中。本次竞争性续展申请的中心假设与前一次申请的中心假设相同。这项应用涉及更多的具体目标，重点是继续我们对乳糜泻的醋酸盐补充疗法的努力，并作为目前研究结果的后续，测试乳糜泻发病机制的其他方面。当前的目标是1)继续我们正在进行的努力，通过慢性GT A给药来纠正CD的醋酸缺乏，并测试其对CD发展的影响；2)表征髓磷脂脂合成的醋酸途径，以进一步了解NAA的功能作用；3)确定在CD中NAA增加的中枢神经系统组织室，作为了解NAA增加在CD病理中的作用的第一步。这些研究可能会带来一种简单而廉价的治疗乳糜泻的方法，并进一步了解NAA的功能作用以及NAA升高与乳糜泻病理的关系。

Canavan disease (CD) is an autosom al-recessive neurodegenerative disorder caused by mutations in the gene coding for the enzyme aspartoacylase (ASPA). ASPA catalyzes deacetylation of N-acetylaspartate (NAA), an abundant (~ 10 mM) and nervous system-specific amino acid derivative. CD is characterized by spongiform degeneration of the brain resulting in severe psychomotor retardation, with most affected children dying before the age of 10. The precise pathogenesis of CD remains unclear. The central hypothesis is that ASPA activity is required for myelin synthesis via liberating the NAA-derived acetate for the synthesis of acetyl CoA, which is used in the synthesis of the lipid portion of myelin. In this hypothesis, CD is thought to result from defective myelin synthesis caused by a deficiency in the supply of the NAA- derived acetate. A number of studies, including our recent demonstration of the selective localization of ASPA in oligodendrocytes in the CNS, are consistent with the acetate deficiency hypothesis of CD. Furthermore, we have recently tested the acetate deficiency hypothesis in the murine model of CD (ASPA -/- ) directly by 1) determining acetate levels in the brain and 2) studying the myelin-associated lipid synthesis. The results showed that in CD mice brain acetate levels decreased by about 80% and synthesis of a number of myelin related lipids also decreased significantly. These results provided the first direct evidence in support of this hypothesis. A major implication of these findings is that acetate supplementation is likely to provide a simple and inexpensive therapeutic approach for CD. Toward this goal, we have made progress by finding that oral administration of glyceryl triacetate (Triacetin), an acetate precursor, caused acetate levels in the brain to increase by about 10- fold in 1-2 hours, and efforts to test whether or not acetate supplementation using glyceryl triacetate is effective as a treatment of CD is in progress. The Central hypothesis of this competitive renewal application remains the same as that of the previous application. This application involves additional specific aims focused on continuing our efforts toward acetate supplementation therapy for CD and testing additional aspects of CD pathogenesis as a follow up to the current findings. The immediate goals are 1) to continue our ongoing efforts to correct the acetate deficiency of CD using chronic GT A administration and to test its effect on the development of CD, 2) to characterize the acetate pathway of myelin lipid synthesis to further understand the functional roles of NAA and 3) to determine the CNS tissue compartments in which NAA is increased in CD as a first step to understand the role of increased NAA in CD pathology. These studies are likely to lead to a simple and inexpensive method for the treatment of CD and also advance our knowledge on the functional roles of NAA and the relationship of increased NAA to CD pathology.