Endogenous Aspartoacylase Expression is Responsive to Glutamatergic Activity in vitro and in vivo
Endogenous Aspartoacylase Expression is Responsive to Glutamatergic Activity in vitro and in vivo
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DOI：
10.1002/glia.21187
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发表时间：
2011-10-01
期刊：
影响因子：
6.2
通讯作者：
Leone, Paola
中科院分区：
文献类型：
--
作者：
Francis, Jeremy S.;Strande, Louise;Leone, Paola
天冬氨酸酰化酶（ASPA）是一种分解代谢神经元氨基酸衍生物N-乙酰-L-天冬氨酸（NAA）的酶。这种功能的丧失导致发育髓鞘形成的失败。NAA的合成和catalysts分别在神经元和少突胶质细胞中被严格区分，并且有证据表明ASPA活性的发育调节是转录的。NAA没有已知的直接生理作用模式，并且ASPA的转录调节因子的鉴定将提供将NAA与相对更特征化的生理环境联系起来的机会，以期确定功能分类。使用转录和免疫组织化学终点，我们定义了一个产后发育窗口，该窗口由大鼠大脑中预先存在的少突胶质细胞群体中aspa的增加所打断。本体论挖掘的表达数据产生的Aspa-空大鼠在此发育窗口识别神经元和少突胶质细胞的转录异常，这表明之间的关联，ASPA的突触活性。谷氨酸，但不是NAA，显示激活内源性aspa表达在体外，和内源性aspa表达上调的动物的大脑中过度表达囊泡谷氨酸转运蛋白I型（vapor 1）。这些结果定义了一个离散的时期内，谷氨酸提供了一种手段，通过这种手段，紧密分隔的NAA代谢周期可以与正常发育同步，并可能是一个因素，在病理模型失调的NAA代谢。(C)2011 Wiley-Liss，Inc.
Aspartoacylase (ASPA) is an enzyme that functions to catabolize the neuronal amino acid derivative N-acetyl-L-aspartic acid (NAA). Loss of this function results in the failure of developmental myelination. NAA synthesis and catabolism are tightly compartmentalized within neurons and oligodendrocytes, respectively, and there is evidence to suggest the developmental regulation of ASPA activity is transcriptional. NAA has no known direct physiological mode of action, and the identification of a transcriptional regulator of aspa would provide an opportunity to link NAA to relatively more characterized physiological contexts with a view to definitive functional classification. Using transcriptional and immunohistochemical endpoints, we define a window of postnatal development punctuated by increases in aspa within a pre-existing population of oligodendrocytes in the rat brain. Ontological mining of expression data generated in aspa-null rats during this developmental window identifies both neuronal and oligodendroglial transcriptional abnormalities that suggest an association between glutamatergic synaptic activity and ASPA. Glutamate, but not NAA, is shown to activate endogenous aspa expression in vitro, and endogenous aspa expression is upregulated in the brains of animals over expressing vesicular glutamate transporter type-I (vglut1). These results define a discrete period of postnatal development within which glutamate provides a means by which the tightly compartmentalized NAA metabolic cycle can function in sync with normal development and may be a factor in pathological models of dysregulated NAA metabolism. (C) 2011 Wiley-Liss, Inc.