Professor Zhang Lining of Shandong University reveals the role of tumor suppressor PDCD4 in depression.

Learn about the latest progress in neuroscience Programmed cell death factor 4 (PDCD4) is a newly discovered tumor suppressor gene related to cell cycle and apoptosis. The protein encoded by PDCD4 can enhance the sensitivity of a variety of tumor cells to anti-tumor drugs and inhibit the occurrence, development, invasion and metastasis of tumors. It is also the first tumor inhibitor found to act on the protein translation stage.PDCD4 can be phosphorylated by S6K1, which is an important downstream effector of mammalian rapamycin target protein (mTOR).at present, there are few studies on PDCD4 in the brain.on March 16, 2020, the research team of Professor Zhang lining from the Department of immunology, School of basic medicine, Shandong University, found that PDCD4 plays a new role in regulating the translation of BDNF mRNA, which is a key molecule in controlling depression.in recent years, Professor Zhang lining has focused on PDCD4 and found its role in many diseases such as colorectal cancer, atherosclerosis, obesity, glioma and so on.in this paper, Professor Zhang extended the role of PDCD4 to depression.researchers found that PDCD4 is widely distributed in the brain, including prefrontal cortex (PFC), hippocampus, hypothalamus, striatum, entorhinal cortex and thalamus, and PDCD4 is mainly produced by neurons. The expression of PDCD4 in hippocampus was significantly up-regulated after chronic restraint stress (a model widely used to induce anxiety and depression in animals), but PFC did not change.is PDCD4 involved in chronic stress-induced depression like behavior? After chronic restraint stress with wild-type mice and PDCD4 knockout mice, the researchers found that the immobility time in forced swimming and tail suspension test of wild-type mice increased significantly after stress, and the consumption rate of sugar water in sugar preference test was also significantly reduced, which indicated that the mice showed obvious depression like behavior, and open field experiment showed that wild-type mice had anxiety like behavior. Br / >the behavior similar to that of depression was not observed in the rats with depression.these results further indicate that PDCD4 knockout mice have resistance to depression like and anxiety like behaviors induced by chronic stress.on the other hand, the researchers used AAV virus to specifically overexpress PDCD4 in the hippocampus, which led to depression like behavior in mice even without chronic stress.these results suggest that PDCD4 is involved in stress-induced depression like behavior.previous studies have shown that the activation of mTORC1 signal promotes the phosphorylation and ubiquitination mediated degradation of PDCD4.molecular analysis showed that the activation of mTORC1 and the phosphorylation and ubiquitination of PDCD4 in hippocampus decreased after chronic restraint stress, which indicated that chronic stress inhibited the degradation of PDCD4 mediated by ubiquitination by reducing the activation of mTORC1. The phosphorylation of PDCD4 inhibited the degradation of PDCD4 mediated by ubiquitination, which finally led to the increase of PDCD4 expression in hippocampus, which to a certain extent answered why PDCD4 expression in hippocampus after stress The expression increased.BDNF plays an important role in improving neural plasticity and antidepressant treatment in the process of depression.the researchers found that BDNF protein expression in hippocampus of wild-type mice was down regulated after chronic stress, but not after PDCD4 knockout.in addition, BDNF protein expression was also down regulated after PDCD4 overexpression in hippocampus. the researchers further constructed PDCD4 flxp mice through CRISPR / cas9, and hybridized with CRE mice to specifically knock out PDCD4 on neurons, which showed antidepressant and anti anxiety effects. In addition, the protein expression of BDNF did not decrease after chronic stress. these results suggest that PDCD4 may inhibit the formation of BDNF and have a negative regulatory effect. using geo database skillfully, the researchers found that the expression level of PDCD4 in hippocampus tissue samples of patients with depression increased after death. this further indicates that PDCD4 may play an important role in promoting the development of depression. based on this finding, they constructed PDCD4 silencing virus, which could reduce the expression of PDCD4. after chronic restraint stress, the above-mentioned silent virus can effectively alleviate depression like behavior in mice. researchers found that PDCD4 inhibited the expression of BDNF in an eIF4A (eukaryotic initiation factor 4a) dependent manner. Therefore, disruption of the relationship between PDCD4 and eIF4A may promote the expression of BDNF and thus play an antidepressant role. the research team has developed a new peptide tat-eif4a, which can effectively destroy the binding of PDCD4 and eIF4A, and promote the expression of BDNF. after chronic stress, tat-eif4a could significantly alleviate depression like and anxiety like behaviors in mice. in conclusion, in this paper, we repeatedly demonstrated the role of PDCD4 in depression through a variety of methods, and independently developed a peptide to block the function of PDCD4 to enhance the expression of BDNF and play an antidepressant role, which indicates that PDCD4 may be a new target for the treatment of depression. original link: