Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease
Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease
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DOI：
10.1016/j.ymthe.2005.01.006
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发表时间：
2005-05-01
影响因子：
12.4
通讯作者：
During, MJ
中科院分区：
文献类型：
--
作者：
Klugmann, M;Leichtlein, CB;During, MJ
卡纳万病是一种早发性脑白质营养不良，与精神发育迟滞、癫痫发作和过早死亡有关。这种疾病是由编码β-淀粉酰化酶（ASPA）的基因突变引起的。正常情况下，ASPA富集在少突胶质细胞中，ASPA缺乏导致其底物分子N-乙酰天冬氨酸（NAA）水平升高、脑水肿和髓鞘形成障碍。使用腺相关病毒，我们永久表达ASPA在震颤大鼠的中枢神经系统神经元，卡纳万病的遗传模型，并通过监测NAA代谢，髓鞘形成，运动行为和癫痫发作检查治疗的疗效。ASPA蛋白和酶活性在整个大脑半球的评估显示恢复到正常水平，长达6个月后治疗。这一发现与NAA水平的降低相关，沿着癫痫发作表型的挽救。然而，大体脑病理学（如脑室扩张和海绵状空泡形成）无变化。此外，ASPA基因转移不能解决髓鞘形成不足和运动缺陷。我们的数据表明，NAA介导的神经元兴奋过度，但少突胶质细胞功能障碍可以补偿神经元ASPA表达。
Canavan disease is an early onset leukodystrophy associated with psychomotor retardation, seizures, and premature death. This disorder is caused by mutations in the gene encoding the enzyme aspartoacylase (ASPA). Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination. Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures. Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment. This finding correlated with a reduction of NAA levels, along with a rescue of the seizure phenotype. However, gross brain pathology, such as dilated ventricles and spongiform vacuolization, was unchanged. Moreover, hypomyelination and motor deficits were not resolved by ASPA gene transfer. Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression.