Modulation of Aldehyde Dehydrogenase Activity Affects (±)-4-Hydroxy-2E-nonenal (HNE) Toxicity and HNE-Protein Adduct Levels in PC12 Cells
Modulation of Aldehyde Dehydrogenase Activity Affects (±)-4-Hydroxy-2E-nonenal (HNE) Toxicity and HNE-Protein Adduct Levels in PC12 Cells
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DOI：
10.1007/s12031-011-9688-y
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发表时间：
2012-07-01
影响因子：
3.1
通讯作者：
Kotraiah, Vinayaka
中科院分区：
文献类型：
--
作者：
Kong, Dehe;Kotraiah, Vinayaka
已知氧化应激是帕金森病（PD）的主要因素之一。氧化应激的后果之一是脂质过氧化。 (+/-)-4-羟基-2E-壬烯醛 (HNE) 是脂质过氧化的有毒产物，会导致膜破裂并形成 HNE-蛋白加合物，并且已在 PD 脑组织中检测到此类加合物。醛脱氢酶 (ALDH) 参与 HNE 和其他内源醛的代谢。有趣的是，据报道，PD 受影响的脑组织中胞浆醛脱氢酶 1A1 (ALDH1A1) 下调，这可能导致 HNE 毒性增强。我们试图通过过表达 ALDH1A1 并使用双硫仑（一种 ALDH 抑制剂）来首先确定 ALDH1A1 在介导 PC12 细胞中 HNE 毒性中的作用。 ALDH1A1 活性的过表达和抑制分别导致 HNE 毒性降低和增加。然后，我们建立了在 HNE 处理后检测 HNE-蛋白加合物的条件，并表明 ALDH 活性的过度表达和抑制分别导致 HNE-蛋白加合物的形成减少和增加。我们还表明，6-甲基-2-(苯基偶氮)-3-吡啶醇（之前被鉴定为 ALDH1A1 的激活剂）可以保护 PC12 细胞免受 HNE 介导的毒性，并可以导致 HNE 蛋白加合物水平小幅但显着降低。我们的结果应该鼓励鉴定更有效的 ALDH 激活剂并在 PC12-HNE 模型中进行测试。然后可以在氧化应激诱导的 PD 体内模型中测试此类细胞保护化合物的神经保护活性。
Oxidative stress is known to be one of the major factors underlying Parkinson's disease (PD). One of the consequences of oxidative stress is lipid peroxidation. A toxic product of lipid peroxidation, (+/-)-4-hydroxy-2E-nonenal (HNE) leads to membrane disruption and formation of HNE-protein adducts and such adducts have been detected in PD brain tissues. Aldehyde dehydrogenases (ALDHs) are involved in metabolizing HNE and other endogenous aldehydes. Interestingly, the cytosolic aldehyde dehydrogenase 1A1 (ALDH1A1) has been reported to be down-regulated in brain tissues affected in PD which could result in enhancement of HNE toxicity. We sought to first establish the role of ALDH1A1 in mediating HNE toxicity in PC12 cells by overexpressing ALDH1A1 and by using disulfiram, an ALDH inhibitor. Overexpression and inhibition of ALDH1A1 activity resulted in reduced and increased HNE toxicity, respectively. We then established conditions for detecting HNE-protein adducts following HNE treatment and showed that overexpression and inhibition of ALDH activity resulted in reduced and increased formation of HNE-protein adducts, respectively. We also show that 6-methyl-2-(phenylazo)-3-pyridinol, previously identified as an activator of ALDH1A1, can protect PC12 cells against HNE-mediated toxicity and can cause a small but significant decrease in levels of HNE-protein adducts. Our results should encourage identification of more potent ALDH activators and their testing in the PC12-HNE model. Such cytoprotective compounds could then be tested for their neuroprotective activity in in vivo models of oxidative stress-induced PD.