ACS Chemical Neuroscience最新文献

Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-26 DOI: 10.1021/acschemneuro.4c00630

Zeynep Nur Cinviz, Ozge Sensoy

{"title":"Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant.","authors":"Zeynep Nur Cinviz, Ozge Sensoy","doi":"10.1021/acschemneuro.4c00630","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00630","url":null,"abstract":"Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease. Therefore, recent efforts have focused on the rescue of defective parkin by engineered proteins or small-molecule activators to enhance parkin activation. These attempts require holistic understanding of the multistep activation mechanism and molecular effects of disease-associated mutations. Hereby, we provided a comprehensive analysis of the activation mechanism of parkin and a clinically relevant mutant, parkinS167N, using molecular dynamics simulations based on the following crystal structures: (1) parkin, (2) parkin/pUb (phosphorylated Ubiquitin), (3) pparkin/pUb, and (4) pparkin/pUb/UbcH7-Ub. Each of these represents an individual step in the activation process. We showed that the mutation impacted the dynamics of not only the RING0 domain, where it is localized, but also the RING2, Ubl, and IBR domains. We identified residues participating in the allosteric interaction network involved in parkin activation. Some of them are mutated in PD-associated parkin variants. The RING0 domain provides a binding interface with various proteins, so understanding problems associated with the mutation paves the way to the discovery of effective engineered proteins or small molecules that activate mutant parkin.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

m6A Demethylase FTO-Mediated Upregulation of BAP1 Induces Neuronal Ferroptosis via the p53/SLC7A11 Axis in the MPP⁺/MPTP-Induced Parkinson's Disease Model.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-23 DOI: 10.1021/acschemneuro.4c00620

Zhengyu Li, Xin Chen, Wenwen Xiang, Ting Tang, Li Gan

{"title":"m6A Demethylase FTO-Mediated Upregulation of BAP1 Induces Neuronal Ferroptosis via the p53/SLC7A11 Axis in the MPP+/MPTP-Induced Parkinson's Disease Model.","authors":"Zhengyu Li, Xin Chen, Wenwen Xiang, Ting Tang, Li Gan","doi":"10.1021/acschemneuro.4c00620","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00620","url":null,"abstract":"Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the involvement of ferroptosis in its pathological mechanism. In this study, the effects and mechanism of BRCA1-associated protein 1 (BAP1) on neuronal ferroptosis in PD were evaluated. Methods: A PD mouse model was constructed by injecting mice with MPTP. Nissl staining, immunohistochemistry, immunofluorescence, and Prussian blue staining evaluated histopathology and iron distribution. The PD cell model was constructed by subjecting SK-N-SH cells to MPP+. The m6A level of BAP1 was assessed by MeRIP. mRNA levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, and SLC7A11 were evaluated utilizing RT-qPCR. Protein levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, SLC7A11, and p53 were measured by Western blot. Cell viability was assessed using CCK-8 assay, and TUNEL was used for assessing apoptosis. The levels of MDA, GSH, SOD, and Fe2+ were also measured. The interactions among molecules were verified using RIP assay, dual luciferase reporter assay, and ChIP assay. Results: SK-N-SH cells treated with MPP+ showed a decrease in overall m6A levels of BAP1. FTO facilitated m6A demethylation of BAP1, leading to an increased level of expression of BAP1. m6A-binding protein, YTHDF2 recognized and decayed methylated mRNA of BAP1, leading to the reduced BAP1 stability. The FTO/BAP1 axis promoted MPP+-induced ferroptosis by suppressing SLC7A11. BAP1, in collaboration with p53, reduced the level of expression of SLC7A11. Knocking down BAP1 mitigated ferroptosis in an MPTP mouse model. Conclusion: m6A-mediated modification of BAP1 regulates neuronal ferroptosis by cooperating with p53 to decrease the level of SLC7A11. Thus, BAP1 may be a potential therapeutic target for PD treatment.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rapid Microwave Fixation of the Brain Reveals Seasonal Changes in the Phosphoproteome of Hibernating Thirteen-Lined Ground Squirrels. 快速微波固定大脑揭示了冬眠十三行地松鼠磷蛋白组的季节性变化。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-22 DOI: 10.1021/acschemneuro.4c00635

Md Shadman Ridwan Abid, Michael J Naldrett, Sophie Alvarez, Catherine D Eichhorn, Matthew T Andrews, James W Checco

{"title":"Rapid Microwave Fixation of the Brain Reveals Seasonal Changes in the Phosphoproteome of Hibernating Thirteen-Lined Ground Squirrels.","authors":"Md Shadman Ridwan Abid, Michael J Naldrett, Sophie Alvarez, Catherine D Eichhorn, Matthew T Andrews, James W Checco","doi":"10.1021/acschemneuro.4c00635","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00635","url":null,"abstract":"Hibernating mammals such as the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) experience significant reductions in oxidative metabolism and body temperature when entering a state known as torpor. Animals entering or exiting torpor do not experience permanent loss of brain function or other injuries, and the processes that enable such neuroprotection are not well understood. To gain insight into changes in protein function that occur in the dramatically different physiological states of hibernation, we performed quantitative phosphoproteomics experiments on thirteen-lined ground squirrels that are summer-active, winter-torpid, and spring-active. An important aspect of our approach was the use of focused microwave irradiation of the brain to sacrifice the animals and rapidly inactivate phosphatases and kinases to preserve the native phosphoproteome. Overall, our results showed pronounced changes in phosphorylated proteins for the transitions into and out of torpor, including proteins involved in gene expression, DNA maintenance and repair, cellular plasticity, and human disease. In contrast, the transition between the active states showed minimal changes. This study offers valuable insight into the global changes in brain phosphorylation in hibernating mammals, the results of which may be relevant to future therapeutic strategies for brain injury.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Serotonergic Mechanisms in Proteinoid-Based Protocells. 基于蛋白的原始细胞中的血清素能机制。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-22 DOI: 10.1021/acschemneuro.4c00801

Panagiotis Mougkogiannis, Andrew Adamatzky

引用次数: 0

Enhanced Analgesic Efficacy and Reduced Side Effects of Morphine by Combination with PD-1 Agonist. 吗啡联合PD-1激动剂增强镇痛效果及减少副作用。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-21 DOI: 10.1021/acschemneuro.4c00732

Xiaofei Song, Ying Zhang, Yuxin Liu, Gang Chen, Long Zhao

引用次数: 0

Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT₇ Receptor Inverse Agonists. 8-羟基-四氢异喹啉类5-HT7受体拮抗剂的合成、药理表征及结合模式分析

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-21 DOI: 10.1021/acschemneuro.4c00667

Camilla B Chan, Eline Pottie, Icaro A Simon, Adrian G Rossebø, Matthias M Herth, Kasper Harpsøe, Jesper L Kristensen, Christophe P Stove, Christian B M Poulie

{"title":"Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists.","authors":"Camilla B Chan, Eline Pottie, Icaro A Simon, Adrian G Rossebø, Matthias M Herth, Kasper Harpsøe, Jesper L Kristensen, Christophe P Stove, Christian B M Poulie","doi":"10.1021/acschemneuro.4c00667","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00667","url":null,"abstract":"The serotonin 7 receptor (5-HT7R) regulates various processes in the central nervous system, including mood, learning, and circadian rhythm control, among others. Receptor activation can lead to activation of the Gαs protein and a subsequent increase of intracellular cyclic adenosine monophosphate (cAMP). Receptor interaction with inverse agonists results in a decrease of basal cAMP levels and therefore a downstream effect of reduced neuronal excitability and neurotransmission. Recently, pellotine (1a), a Lophophora alkaloid, was unexpectedly shown to be an inverse agonist of the 5-HT7R. Therefore, we evaluated close analogs of compound 1a, both naturally occurring and synthetic analogs, as inverse agonists of the 5-HT7R. Functional evaluation in a GloSensor cAMP assay revealed a preference for an 8-hydroxy-6,7-dimethoxy substitution pattern over 6,7,8-trimethoxy analogs or 8-hydroxy-6,7-methylenedioxy analogs. This was supported by molecular dynamics simulations, where the 8-hydroxy substitution allowed more robust interaction with the 5-HT7R, which correlated with inverse agonism efficacy. Additionally, N-methylation (as in 1a) improved the potency of the evaluated analogs. In this series, the most potent inverse agonist was anhalidine (1b) (EC50 = 219 nM, Emax = -95.4%), which lacks the 1-methyl, compared to pellotine (1a), and showed a 2-fold higher functional potency. Altogether, these results provide key insights for the further development of potent low molecular weight inverse agonists of the 5-HT7R.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hinokinin Decreases Methamphetamine-Induced Hyperlocomotion via the Regulatory Effects on Dopamine Levels. Hinokinin通过对多巴胺水平的调节作用减少甲基苯丙胺诱导的过度运动。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-21 DOI: 10.1021/acschemneuro.4c00592

Byoung Mo Choi, Sun Mi Gu, Abdulaziz Jabborov, Min-Seok Yang, Sang Won Yeon, Chun-Woong Park, Mi Kyeong Lee, Jaesuk Yun

{"title":"Hinokinin Decreases Methamphetamine-Induced Hyperlocomotion via the Regulatory Effects on Dopamine Levels.","authors":"Byoung Mo Choi, Sun Mi Gu, Abdulaziz Jabborov, Min-Seok Yang, Sang Won Yeon, Chun-Woong Park, Mi Kyeong Lee, Jaesuk Yun","doi":"10.1021/acschemneuro.4c00592","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00592","url":null,"abstract":"The global abuse of stimulant methamphetamine (METH) imposes a significant social burden. Despite this, effective therapeutic interventions for mitigating the harmful effects associated with METH-induced central nervous system (CNS) stimulation remain elusive. Chamaecyparis obtusa (hinoki), containing hinokinin as its active constituent, has been identified to exhibit CNS depressant properties. Here, we explored the potential of the hinoki extract and hinokinin in modulating METH-induced hyperlocomotion through the regulation of dopaminergic neuronal activity. We discovered that pretreatment with hinokinin significantly attenuates METH-induced locomotor activity, indicative of reduced CNS stimulation. Furthermore, treatment with hinokinin was observed to inhibit the METH-induced elevation in dopamine levels and the concomitant decrease in dopamine transporter (DAT) function within striatal brain slices of mice. In silico analysis coupled with pull-down assays and the dose-response curve substantiated the direct binding of hinokinin to DAT. We propose that hinokinin mitigates METH-induced hyperlocomotion via the inhibition of dopaminergic neurotransmission, with allosteric modulation of DAT playing a critical role in this regulatory mechanism. Collectively, our research suggests the potential of hinokinin to mitigate dopamine-mediated central nervous system excitation.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unlocking Neuroinflammation: A Balanced Art for Therapeutics of Prion Disease. 解锁神经炎症：朊病毒疾病治疗的平衡艺术。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-21 DOI: 10.1021/acschemneuro.4c00871

Cao Chen, Xiaoping Dong

引用次数: 0

Targeted Metabolomics for the Analysis of p-Cresol in Mouse Brain: Impact of Biological Sex and Strain. 小鼠脑内对甲酚的代谢组学分析：生物性别和品系的影响。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-19 DOI: 10.1021/acschemneuro.4c00698

Laura Bertarini, Federico Imbeni, Antonietta Vilella, Silvia Alboni, Federica Pellati

{"title":"Targeted Metabolomics for the Analysis of p-Cresol in Mouse Brain: Impact of Biological Sex and Strain.","authors":"Laura Bertarini, Federico Imbeni, Antonietta Vilella, Silvia Alboni, Federica Pellati","doi":"10.1021/acschemneuro.4c00698","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00698","url":null,"abstract":"p-Cresol, an environmental contaminant and endogenous metabolite derived primarily from the conversion of l-tyrosine by intestinal microflora, is gaining increasing attention, due to its potential impact on human health. Recent studies have highlighted elevated levels of p-cresol and its metabolites, including p-cresyl sulfate and p-cresyl glucuronide, in various populations, suggesting a correlation with neurodevelopmental and neurodegenerative conditions. While the role of this compound as a uremic toxin is well established, its presence and concentration within the central nervous system (CNS) remain largely unexplored. To address this gap, an high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was optimized and validated for the first time in this work for the targeted metabolomics of p-cresol in brain tissues. This method enabled the quantification of this compound in different brain areas of adult male and female C57BL/6J mice and in the cortex of various mouse strains, including CD-1 and the idiopathic autism model BTBR T+Itpr3tf/J. Additionally, preliminary analyses of human cortex samples confirmed the presence of p-cresol, suggesting its relevance in human brain health. Moreover, metabolomic analyses have further explored the correlations between p-cresol and neurotransmitters, with a particular focus on dopaminergic and noradrenergic pathways. These findings pave the way for understanding the potential impact of p-cresol on neurochemical networks and its implications for neurodevelopmental and neurodegenerative disorders.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reactivity of Olanzapine and Tricyclic Antidepressants on the Protective Effects of Trolox on Lipid Peroxidation Evaluated Using Fluorescence Anisotropy, Electron Paramagnetic Resonance Spectrometry, and Thermal Analysis. 利用荧光各向异性、电子顺磁共振光谱和热分析评价奥氮平和三环抗抑郁药对曲洛克斯脂质过氧化保护作用的反应性。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-01-17 DOI: 10.1021/acschemneuro.4c00702

Yusuke Horizumi, Reo Tanada, Yuya Kurosawa, Miwa Takatsuka, Tomohiro Tsuchida, Satoru Goto

{"title":"Reactivity of Olanzapine and Tricyclic Antidepressants on the Protective Effects of Trolox on Lipid Peroxidation Evaluated Using Fluorescence Anisotropy, Electron Paramagnetic Resonance Spectrometry, and Thermal Analysis.","authors":"Yusuke Horizumi, Reo Tanada, Yuya Kurosawa, Miwa Takatsuka, Tomohiro Tsuchida, Satoru Goto","doi":"10.1021/acschemneuro.4c00702","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00702","url":null,"abstract":"Multiacting receptor-targeting antipsychotics and tricyclic antidepressants stimulate various neurotransmitter receptors despite the different targets of postsynaptic receptors and presynaptic reuptake transporters. Their auxiliary and adverse effects may be caused by multiple targets or the modification of the neuronal membrane. To evaluate the membrane responses to olanzapine, imipramine, desipramine, amitriptyline, lidocaine, and dibucaine, we examined the inhibition of lipid peroxidation in egg yolk phosphatidylcholine liposomes. By contrast, their effects on membrane fluidity were measured as the suppressive contributions of the inhibitory activity of Trolox on lipid oxidation. These drugs inhibit lipid peroxidation and exclude harmful reactive oxygen species and the protective effect of Trolox. The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in saturated phospholipid liposome-containing drugs suggested that olanzapine, imipramine, and dibucaine enhanced membrane fluidity. The radical scavenging activity of 2,2-diphenylpicrylhidrazyl and galvinoxyl radicals was determined using electron paramagnetic resonance experiments, and their molecular flexibility was determined using thermograms for differential scanning calorimetry. Multiple regression analyses of the linear free energy relationship approach and comparative investigations revealed that the membranous fluidity of the liposomes, independent of the radical scavenging activity of the drugs, induced the inhibitory activity on lipid peroxidation. We discussed how these drugs act on nervous membranes and aimed to identify the relationship between uncertified functions and membranous fluidity.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0