Functional significance of aldehyde dehydrogenase ALDH1A1 to the nigrostriatal dopamine system.
Functional significance of aldehyde dehydrogenase ALDH1A1 to the nigrostriatal dopamine system.
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DOI：
10.1016/j.brainres.2011.06.051
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发表时间：
2011-08-23
期刊：
影响因子：
2.9
通讯作者：
Schneider JS
中科院分区：
文献类型：
--
作者：
Anderson DW;Schray RC;Duester G;Schneider JS
乙醛脱氢酶1A 1（ALDH 1A 1）是在各种组织中发现的解毒酶超家族的成员，其参与脂肪族和芳香族醛的氧化。在脑中，ALDH 1A 1参与包括多巴胺（DA）和去甲肾上腺素的儿茶酚胺的代谢，但在腹侧中脑中的多巴胺能（DA能）神经元的子集中独特地表达，在腹侧中脑中，ALDH 1A 1将3，4-二羟基苯乙醛（一种潜在有毒的醛）转化为3，4-二羟基苯乙酸（一种无毒代谢物）。因此，可以预测ALDH 1A 1表达的丧失会改变DA代谢，并可能增加腹侧中脑DA神经元的神经毒性。最近的报告显示，帕金森病患者黑质（SN）中Aldh 1a 1 mRNA和蛋白表达水平降低，这表明ALDH 1A 1可能参与了这种进行性神经退行性疾病。本研究使用ALDH 1A 1敲除小鼠评估ALDH 1A 1对DA能系统功能和维持的影响。结果表明，Aldh 1a 1的缺失不会对SN DA神经元的生长和发育产生负面影响，也不会改变酪氨酸羟化酶、DA转运蛋白或囊泡单胺转运蛋白2的蛋白表达水平。然而，缺乏Aldh 1a 1显着增加基础细胞外DA水平，减少KCl和安非他明刺激DA释放和减少DA再摄取，导致更多的酪氨酸羟化酶表达神经元的SN比野生型动物。这些数据表明，在年轻的成年动物与Aldh 1a 1基因的缺失有改变DA代谢和功能障碍的DA转运蛋白和DA释放机制。
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of a superfamily of detoxification enzymes found in various tissues that participate in the oxidation of both aliphatic and aromatic aldehydes. In the brain, ALDH1A1 participates in the metabolism of catecholamines including dopamine (DA) and norepinephrine, but is uniquely expressed in a subset of dopaminergic (DAergic) neurons in the ventral mesencephalon where it converts 3,4-dihydroxyphenylacetaldehyde, a potentially toxic aldehyde, to 3,4-dihydroxyphenylacetic acid, a non toxic metabolite. Therefore, loss of ALDH1A1 expression could be predicted to alter DA metabolism and potentially increase neurotoxicity in ventral mesencephalic DA neurons. Recent reports of reduced levels of expression of both Aldh1a1 mRNA and protein in the substantia nigra (SN) of Parkinson's disease patients suggest possible involvement of ALDH1A1 in this progressive neurodegenerative disease. The present study used an Aldh1a1 null mouse to assess the influence of ALDH1A1 on the function and maintenance of the DAergic system. Results indicate that the absence of Aldh1a1 did not negatively affect growth and development of SN DA neurons nor alter protein expression levels of tyrosine hydroxylase, the DA transporter or vesicular monoamine transporter 2. However, absence of Aldh1a1 significantly increased basal extracellular DA levels, decreased KCl and amphetamine stimulated DA release and decreased DA re-uptake and resulted in more tyrosine hydroxylase expressing neurons in the SN than in wildtype animals. These data suggest that in young adult animals with deletion of the Aldh1a1 gene there is altered DA metabolism and dysfunction of the DA transporter and DA release mechanisms.
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