Alterations in Phosphatidylinositol 3-Kinase Activity and PTEN Phosphatase in the Prefrontal Cortex of Depressed Suicide Victims
Alterations in Phosphatidylinositol 3-Kinase Activity and PTEN Phosphatase in the Prefrontal Cortex of Depressed Suicide Victims
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DOI：
10.1159/000322145
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发表时间：
2011-01-01
影响因子：
3.2
通讯作者：
Malafosse, Alain
中科院分区：
文献类型：
--
作者：
Karege, Felicien;Perroud, Nader;Malafosse, Alain
背景资料：最近的研究报道了蛋白激酶B（PKB）/Akt及其下游靶点糖原合成酶激酶3 β在抑郁症和自杀中的改变。本研究的目的是调查可能的损害的上游调节，即磷脂酰肌醇3-激酶（PI 3 K）和PTEN。方法：24名自杀者和24名未服药的非自杀者的腹侧前额叶皮层（布罗德曼11区）。从机构记录或心理尸检中获得重度抑郁症的生前诊断，并进行毒理学分析。采用免疫印迹法测定PI 3 K和PTEN蛋白水平，并通过特异性底物的磷酸化测定PI 3 K和Akt的激酶活性。结果如下：在抑郁症自杀者和抑郁症非自杀受试者中，观察到PI 3 K [ANOVA：F（3，44）= 9.20; p < 0.001]和Akt 1 [ANOVA：F（3，44）= 13.59; p < 0.001]的酶活性降低，而蛋白质水平没有任何变化（分别为p < 0.01和p < 0.002）。在相同的组中，PTEN蛋白水平增加[ANOVA：F（3，44）= 10.5; p < 0.001]。在非抑郁的自杀受害者中没有观察到变化。结论：这项研究的结论是，在抑郁症自杀受害者的PKB/Akt激酶活性的衰减可能是由于PTEN和PI 3 K的组合失调，导致脂质第二信使磷酸化不足。这种效应与严重抑郁症有关，而不是与自杀本身有关。鉴于在抑郁症中报道的细胞缺陷，参与细胞存活和神经可塑性的酶的研究与抑郁症中的神经营养因子失调特别相关。版权所有（C）2011 S. Karger AG，巴塞尔
Background: Recent studies have reported alterations in protein kinase B (PKB)/Akt and in its downstream target, glycogen synthase kinase 3 beta, in depression and suicide. The aim of the present study was to investigate possible impairment of the upstream regulators, namely phosphatidylinositol 3-kinase (PI3K) and PTEN. Methods: The ventral prefrontal cortex (Brodmann's area 11) of 24 suicide victims and 24 drug-free nonsuicide subjects was used. The antemortem diagnoses of major depression disorder were obtained from the institutional records or psychological autopsy, and toxicological analyses were performed. Protein levels of PI3K and PTEN were assayed using the immunoblot method, and the kinase activity of PI3K and Akt was determined by phosphorylation of specific substrates. Results: A decrease was observed in the enzymatic activity of PI3K [ANOVA: F(3, 44) = 9.20; p < 0.001] and Akt1 [ANOVA: F(3, 44) = 13.59; p < 0.001], without any change in protein levels, in both depressed suicide victims and depressed nonsuicide subjects (p < 0.01 and p < 0.002, respectively). PTEN protein levels were increased in the same groups [ANOVA: F(3, 44) = 10.5; p < 0.001]. No change was observed in nondepressed suicide victims. Conclusion: This study concludes that attenuation of kinase activity of PKB/Akt in depressed suicide victims may be due to the combined dysregulation of PTEN and PI3K resulting in insufficient phosphorylation of lipid second messengers. The effect is associated with major depression rather than with suicide per se. Given the cellular deficits reported in major depression, the study of enzymes involved in cell survival and neuroplasticity is particularly relevant to neurotrophic factor dysregulation in depression. Copyright (C) 2011 S. Karger AG, Basel