Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du
{"title":"定量蛋白质组学结合独立的 PRM 分析揭示了去甲异博定抗抑郁作用的线粒体和突触机制。","authors":"Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du","doi":"10.1038/s41398-024-03127-z","DOIUrl":null,"url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS<sub>CON</sub>), imipramine (IMI)-treated versus CSDS (IMI<sub>CSDS</sub>), and NOR-treated versus CSDS (NOR<sub>CSDS</sub>) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR<sub>CSDS</sub> groups and NOR<sub>IMI</sub> groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR<sub>CSDS</sub> and NOR<sub>IMI,</sub> revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"400"},"PeriodicalIF":5.8000,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447221/pdf/","citationCount":"0","resultStr":"{\"title\":\"Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.\",\"authors\":\"Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du\",\"doi\":\"10.1038/s41398-024-03127-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS<sub>CON</sub>), imipramine (IMI)-treated versus CSDS (IMI<sub>CSDS</sub>), and NOR-treated versus CSDS (NOR<sub>CSDS</sub>) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR<sub>CSDS</sub> groups and NOR<sub>IMI</sub> groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR<sub>CSDS</sub> and NOR<sub>IMI,</sub> revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.</p>\",\"PeriodicalId\":23278,\"journal\":{\"name\":\"Translational Psychiatry\",\"volume\":\"14 1\",\"pages\":\"400\"},\"PeriodicalIF\":5.8000,\"publicationDate\":\"2024-10-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447221/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Translational Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41398-024-03127-z\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41398-024-03127-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
引用次数: 0
摘要
重度抑郁症(MDD)是一种常见疾病,影响着全球 3 亿人。现有药物对大约 30% 的患者无效,因此开发具有新机制的新型抗抑郁药物迫在眉睫。在这里,我们发现诺异波定(NOR)在慢性社会挫败应激(CSDS)抑郁模型的尾悬、强迫游泳和蔗糖消耗试验中显示出抗抑郁疗效。然后,我们利用药物治疗 CSDS 小鼠范例,从前额叶皮层分离并获得了 CSDS 与 CON(CSDSCON)、丙咪嗪(IMI)治疗与 CSDS(IMICSDS)以及 NOR 治疗与 CSDS(NORCSDS)的不同蛋白质组。这些蛋白质表达的变化首先通过方差分析进行了分析,CSDS 组和 NORIMI 组的 p 支持方差分析的结果。我们采用蛋白质-蛋白质相互作用(PPI)分析来研究 NORCSDS 和 NORIMI 的蛋白质,结果显示与线粒体核糖体和突触功能相关的蛋白质得到了富集。利用平行反应监测(PRM)进行的进一步独立分析表明,Cox7c、Mrp142、Naa30、Ighm、Apoa4、Ssu72、Mrps30、Apoh、Acbd5 和 Cdv3 在 NOR 处理组中表现出调节作用,以支持线粒体功能的平衡。此外,还观察到 Dcx、Arid1b、Rnf112 和 Fam3c 也在 NOR 处理组中受到调节,以支持突触的形成和功能。这些发现表明,参与抑郁治疗的蛋白质具有增强小鼠前脑功能区线粒体和突触功能的作用。Western印迹分析表明,CSDS小鼠体内Mrpl42、Cox7c、Naa30、Rnf112、Dcx Apoa4、Apoh和Fam3c的水平发生了改变,而NOR治疗可以挽救这些改变,这支持了PRM数据。NOR 治疗还能缓解 CSDS 小鼠 NLRP3 炎性体的激活。总之,目前对前额叶皮层进行的蛋白质组学研究为CSDS诱导的抑郁症的病理生理学和治疗提供了有价值的见解,揭示了诺力索波定的治疗效果。
Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NORCSDS groups and NORIMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NORCSDS and NORIMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.
期刊介绍:
Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.