Oxidative Damage of Tryptophan Hydroxylase-2 Mediated by Peroxisomal Superoxide Anion Radical in Brains of Mouse with Depression,Journal of the American Chemical Society

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Oxidative Damage of Tryptophan Hydroxylase-2 Mediated by Peroxisomal Superoxide Anion Radical in Brains of Mouse with Depression
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-11-25 , DOI: 10.1021/jacs.0c09576
Qi Ding ₁ , Ying Tian ₁ , Xin Wang ₁ , Ping Li ₁ , Di Su ₁ , Chuanchen Wu ₁ , Wen Zhang ₁ , Bo Tang ₁

Affiliation

Depression is intimately linked with oxidative stress in the brains. Peroxisome plays vital roles in the regulation of intracellular redox balance by keeping reactive oxygen species (ROS) homeostasis. Available evidence indicates a possible relationship between peroxisomal ROS and depression. Even so, the underlying modulation mechanisms of peroxisomal ROS in depression are still rudimentary due to the limitations of the existing detecting methods. Hence, we developed a two-photon fluorescent probe TCP for the real-time visualization of the first produced ROS superoxide anion radical (O2•-) in peroxisome. Using the two-photon fluorescence imaging, we found that peroxisomal O2•- rose during oxidative stress in the mouse brains, resulting in the inactivation of catalase (CAT). Subsequently, the intracellular H2O2 level elevated, which further oxidized tryptophan hydroxylase-2 (TPH2). Then the decrease contents of TPH2 caused the dysfunction of 5-hydroxytryptamine (5-HT) system in the mouse brains, eventually leading to depression-like behaviors. Our work provides evidence of a peroxisomal O2•- mediated signaling pathway in depression, which will conduce to pinpoint potential targets for the treatment of depression.

中文翻译：

过氧化物酶体超氧化物阴离子自由基介导的色氨酸羟化酶2氧化损伤小鼠抑郁症脑组织

抑郁症与大脑中的氧化应激密切相关。过氧化物酶体通过保持活性氧 (ROS) 稳态在调节细胞内氧化还原平衡中发挥重要作用。现有证据表明过氧化物酶体 ROS 与抑郁症之间可能存在关系。即便如此，由于现有检测方法的局限性，抑郁症中过氧化物酶体 ROS 的潜在调节机制仍然不成熟。因此，我们开发了一种双光子荧光探针 TCP，用于实时可视化过氧化物酶体中第一个产生的 ROS 超氧阴离子自由基 (O2•-)。使用双光子荧光成像，我们发现过氧化物酶体O2•-在小鼠大脑中的氧化应激过程中升高，导致过氧化氢酶（CAT）失活。随后，细胞内 H2O2 水平升高，进一步氧化色氨酸羟化酶-2 (TPH2)。然后TPH2含量减少导致小鼠大脑中5-羟色胺（5-HT）系统功能障碍，最终导致抑郁样行为。我们的工作提供了抑郁症中过氧化物酶体 O2• 介导的信号通路的证据，这将有助于确定治疗抑郁症的潜在目标。

更新日期：2020-11-25

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