N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time
N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time
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DOI：
10.1523/jneurosci.1056-15.2015
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发表时间：
2015-10-28
影响因子：
5.3
通讯作者：
Eckhardt, Matthias
中科院分区：
文献类型：
--
作者：
Maier, Helena;Wang-Eckhardt, Lihua;Eckhardt, Matthias
卡纳万病（Canavan disease，CD）是一种严重的、致死性脑白质营养不良，由水解N-乙酰天冬氨酸（NAA）的天冬酰化酶（ASPA）缺乏引起。在CD患者的大脑中，NAA积累到高毫摩尔浓度。该疾病的病理学特征是CNS中少突胶质细胞的损失和海绵状髓鞘变性。是否积累NAA，缺乏NAA衍生的乙酸，或缺乏任何未知的功能的ASPA酶是负责疾病的病理尚未完全了解。我们产生了ASPA缺陷（Aspa（nur 7/nur 7））小鼠，其也缺乏NAA合酶Nat 8L（Nat 8L（-/-）/Aspa（nur 7/nur 7））。这些小鼠没有可检测到的NAA。然而，他们表现出正常的髓鞘含量，髓鞘鞘脂组成，海绵状髓鞘和轴突变性的完全逆转。令人惊讶的是，尽管病理学完全逆转，但小鼠的存活时间并没有延长。相比之下，只有一个完整的Nat 8L等位基因的Aspa（nur 7/nur 7）小鼠积累了较少的NAA，发展了不太严重的病理，表型改善，重要的是，几乎正常的生存时间。因此，抑制NAA合成酶是CD的一种有希望的治疗选择。然而，Nat 8L（-/-）/Aspa（nur 7/nur 7）小鼠存活率的降低表明，NAA合酶的完全抑制可能会给患者带来不可预见的风险。此外，我们表明，乙酸来源于NAA是不是髓鞘脂质合成所必需的，和NAA衍生的乙酸的损失不会导致Aspa（nur 7/nur 7）小鼠的髓鞘表型。我们的数据清楚地支持这一假设，NAA的积累是CD的发展的主要因素。
Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood. We generated ASPA-deficient (Aspa(nur7/nur7)) mice that are also deficient for NAA synthase Nat8L (Nat8L(-/-)/Aspa(nur7/nur7)). These mice have no detectable NAA. Nevertheless, they exhibited normal myelin content, myelin sphingolipid composition, and full reversal of spongy myelin and axonal degeneration. Surprisingly, although pathology was fully reversed, the survival time of the mice was not prolonged. In contrast, Aspa(nur7/nur7) mice with only one intact Nat8L allele accumulated less NAA, developed a less severe pathology, phenotypic improvements, and, importantly, an almost normal survival time. Therefore, inhibition of NAA synthase is a promising therapeutic option for CD. The reduced survival rate of Nat8L(-/-)/Aspa(nur7/nur7) mice, however, indicates that complete inhibition of NAA synthase may bear unforeseeable risks for the patient. Furthermore, we demonstrate that acetate derived from NAA is not essential for myelin lipid synthesis and that loss of NAA-derived acetate does not cause the myelin phenotype of Aspa(nur7/nur7) mice. Our data clearly support the hypothesis that NAA accumulation is the major factor in the development of CD.