N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase.
N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase.
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DOI：
10.1016/j.nbd.2016.10.001
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发表时间：
2016-12
影响因子：
6.1
通讯作者：
Leone, Paola
中科院分区：
文献类型：
--
作者：
Francis, Jeremy S.;Wojtas, Ireneusz;Markov, Vladimir;Gray, Steven J.;McCown, Thomas J.;Samulski, R. Jude;Bilaniuk, Larissa T.;Wang, Dah-Jyuu;De Vivo, Darryl C.;Janson, Christopher G.;Leone, Paola
神经胶质细胞N-乙酰-天冬氨酸（NAA）代谢的破坏导致发育性髓鞘形成的失败，表现在先天性小儿脑白质营养不良Canavan病中，该疾病由唯一的NAA分解代谢酶β-乙酰基酰化酶突变引起。卡纳万病是一个主要的焦点，努力定义NAA的功能，与现有的证据表明，NAA作为一个乙酰供体的脂肪酸合成髓鞘形成过程中。NAA升高是Canavan病的诊断标志，这与广泛的替代性神经退行性背景形成对比，其中NAA水平与病理进展成反比。最近在Canavan病的nur 7小鼠模型中产生的数据表明，在少突胶质细胞死亡、髓鞘含量异常、海绵状变性和运动缺陷之前，β-酰化酶功能的丧失导致能量完整性受损。本研究利用下一代寡嗜性腺相关病毒载体（AAV-Olig 001）定量评估乙酰化酶重建对发育髓鞘形成的影响。AAV-Olig 001-腺苷酰化酶促进NAA的正常化，增加生物可利用的乙酰辅酶A，并在大体组织病理学和运动功能恶化之前的出生后发育窗口内恢复能量平衡。长期效应包括少突胶质细胞数量增加、髓鞘形成全面增加、空泡化逆转和运动功能恢复。在AAV-Olig 001-乙酰化酶基因治疗后观察到的对脑能量的影响显示与在卡纳万病的轻度病例中观察到的代谢谱一致，暗示NAA在髓鞘形成期间通过少突胶质细胞乙酰化酶维持能量完整性。
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression. Recently generated data in the nur7 mouse model of Canavan disease suggests loss of aspartoacylase function results in compromised energetic integrity prior to oligodendrocyte death, abnormalities in myelin content, spongiform degeneration, and motor deficit. The present study utilized a next-generation “oligotropic” adeno-associated virus vector (AAV-Olig001) to quantitatively assess the impact of aspartoacylase reconstitution on developmental myelination. AAV-Olig001-aspartoacylase promoted normalization of NAA, increased bioavailable acetyl-CoA, and restored energetic balance within a window of postnatal development preceding gross histopathology and deteriorating motor function. Long-term effects included increased oligodendrocyte numbers, a global increase in myelination, reversal of vacuolation, and rescue of motor function. Effects on brain energy observed following AAV-Olig001-aspartoacylase gene therapy are shown to be consistent with a metabolic profile observed in mild cases of Canavan disease, implicating NAA in the maintenance of energetic integrity during myelination via oligodendroglial aspartoacylase.
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