Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt
Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt
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DOI：
10.1096/fj.11-194100
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发表时间：
2012-04-01
期刊：
影响因子：
4.8
通讯作者：
Ravindranath, Vijayalakshmi
中科院分区：
文献类型：
--
作者：
Durgadoss, Lalitha;Nidadavolu, Prakash;Ravindranath, Vijayalakshmi
Akt磷酸化是一种重要的生存信号，其受损与帕金森病中多巴胺能神经元的变性有关。然而，pAkt丢失的潜在机制尚不清楚。在目前的研究中，我们证明了与仅用载体处理的对照小鼠的腹侧中脑相比，用多巴胺能神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）处理的小鼠的腹侧中脑中的pAkt损失。Akt中关键半胱氨酸的巯基残基在用MPTP处理的小鼠中被氧化至更大程度，这反映为还原的Akt损失40%。MPTP处理后，氧化修饰的Akt与磷酸酶PP 2A的结合显著增强，这可导致pAkt的去磷酸化增强。通过巯基抗氧化剂维持蛋白巯基稳态防止了还原型Akt的损失，减少了与PP 2A的结合，并维持了pAkt水平。谷氧还蛋白（一种蛋白质二硫键氧化还原酶）在人原代神经元中的过表达有助于维持Akt的还原状态，并消除MPP+介导的pAkt丢失。我们第一次证明了Akt活性的选择性丧失，在体内，由于Akt的氧化修饰，并提供机制洞察氧化应激诱导的细胞存活途径在小鼠中脑暴露于MPTP后下调。杜尔加多斯湖Nidadavolu，P.，Khader Valli，R.，赛义德，美国，米什拉，M.，Seth，P.，拉温德拉纳特河在小鼠中脑中，由多巴胺能神经毒素MPTP介导的Akt的氧化还原修饰导致pAkt的下调。FASEB J.26，1473-1483（2012）。www.fasebj.org
Impairment of Akt phosphorylation, a critical survival signal, has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. However, the mechanism underlying pAkt loss is unclear. In the current study, we demonstrate pAkt loss in ventral midbrain of mice treated with dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when compared to ventral midbrain of control mice treated with vehicle alone. Thiol residues of the critical cysteines in Akt are oxidized to a greater degree in mice treated with MPTP, which is reflected as a 40% loss of reduced Akt. Association of oxidatively modified Akt with the phosphatase PP2A, which can lead to enhanced dephosphorylation of pAkt, was significantly stronger after MPTP treatment. Maintaining the protein thiol homeostasis by thiol antioxidants prevented loss of reduced Akt, decreased association with PP2A, and maintained pAkt levels. Overexpression of glutaredoxin, a protein disulfide oxidoreductase, in human primary neurons helped sustain reduced state of Akt and abolished MPP+-mediated pAkt loss. We demonstrate for the first time the selective loss of Akt activity, in vivo, due to oxidative modification of Akt and provide mechanistic insight into oxidative stress-induced down-regulation of cell survival pathway in mouse midbrain following exposure to MPTP.-Durgadoss, L., Nidadavolu, P., Khader Valli, R., Saeed, U., Mishra, M., Seth, P., Ravindranath, R. Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt. FASEB J. 26, 1473-1483 (2012). www.fasebj.org