Canavan Disease: Pathogenesis and Treatment

Canavan病(CD)是一种常染色体隐性遗传性神经退行性疾病，由天冬氨酸氨基转移酶(ASPA)编码基因突变引起。ASPA催化N-乙酰天冬氨酸(NAA)的脱乙酰化，N-乙酰天冬氨酸是一种丰富的(~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，大多数受影响的儿童在10岁之前死亡。CD的确切发病机制尚不清楚。中心假设是，髓鞘合成需要ASPA活性，因为它通过释放NAA衍生的乙酸酯来合成乙酰辅酶A，乙酰辅酶A用于合成髓鞘脂类部分。在这个假说中，CD被认为是由于NAA衍生的醋酸盐供应不足而导致的髓鞘合成缺陷所致。许多研究，包括我们最近证明ASPA在中枢神经系统少突胶质细胞中的选择性定位，与CD的醋酸盐缺乏假说是一致的。此外，我们最近在CD小鼠模型(ASPA-/-)中直接测试了醋酸盐缺乏假说，方法是：1)测定大脑中的醋酸盐水平；2)研究髓鞘相关的脂质合成。结果表明，在CD小鼠中，脑醋酸盐水平下降了约80%，许多髓鞘相关脂质的合成也显着减少。这些结果为支持这一假说提供了第一个直接证据。这些发现的一个主要含义是，醋酸盐补充剂可能为CD提供一种简单且廉价的治疗方法。为了实现这一目标，我们取得了进展，发现口服三醋酸甘油酯(三醋酸甘油酯)，一种醋酸盐前体，导致大脑中的醋酸盐水平在1-2小时内增加约10倍，并努力测试使用三醋酸甘油酯补充醋酸盐是否有效，作为CD的治疗正在进行中。这次竞争性续签申请的中心假设与上一次申请的中心假设相同。这项申请涉及更多的具体目标，重点是继续我们对CD的醋酸盐补充治疗的努力，并测试CD发病机制的其他方面，作为当前发现的后续。近期的目标是1)继续我们正在进行的努力，以纠正Cd的醋酸盐缺乏使用慢性GTA，并测试其对Cd的发展的影响，2)表征髓鞘脂合成的醋酸盐途径，以进一步了解NAA的功能作用，3)确定Cd中NAA增加的中枢组织区，作为了解NAA增加在Cd病理中的作用的第一步。这些研究可能会为CD的治疗提供一种简单、廉价的方法，并促进我们对NAA的功能作用以及NAA升高与CD病理的关系的了解。

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.