College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People's Republic of China.
J Am Chem Soc. 2020 Dec 9;142(49):20735-20743. doi: 10.1021/jacs.0c09576. Epub 2020 Nov 25.
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 (O) in peroxisome. Using the two-photon fluorescence imaging, we found that peroxisomal O rose during oxidative stress in the mouse brains, resulting in the inactivation of catalase (CAT). Subsequently, the intracellular HO 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 O mediated signaling pathway in depression, which will conduce to pinpoint potential targets for the treatment of depression.
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）的内环境平衡，在调节细胞内氧化还原平衡方面发挥着重要作用。现有证据表明，过氧化物酶体 ROS 与抑郁症之间可能存在关联。即便如此，由于现有检测方法的局限性，过氧化物酶体 ROS 在抑郁症中的潜在调节机制仍处于初级阶段。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（O）。通过双光子荧光成像，我们发现过氧化物酶体中的 O 在小鼠大脑的氧化应激过程中增加，导致过氧化氢酶（CAT）失活。随后，细胞内的 HO 水平升高，进一步氧化色氨酸羟化酶-2（TPH2）。然后，TPH2 含量的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。我们的工作为抑郁症中过氧化物酶体 O 介导的信号通路提供了证据，这将有助于确定治疗抑郁症的潜在靶点。
