Molecular Neurobiology最新文献_第4页

Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer's Disease. 针对阿尔茨海默病过渡金属（铜、铁和锌）的最新研究进展。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-29 DOI: 10.1007/s12035-024-04256-8

Raghuraj Singh, Archna Panghal, Krishna Jadhav, Ashima Thakur, Rahul Kumar Verma, Charan Singh, Manoj Goyal, Jayant Kumar, Ajay G Namdeo

{"title":"Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer's Disease.","authors":"Raghuraj Singh, Archna Panghal, Krishna Jadhav, Ashima Thakur, Rahul Kumar Verma, Charan Singh, Manoj Goyal, Jayant Kumar, Ajay G Namdeo","doi":"10.1007/s12035-024-04256-8","DOIUrl":"10.1007/s12035-024-04256-8","url":null,"abstract":"Changes in the transition metal homeostasis in the brain are closely linked with Alzheimer's disease (AD), including intraneuronal iron accumulation and extracellular copper and zinc pooling in the amyloid plague. The brain copper, zinc, and iron surplus are commonly acknowledged characteristics of AD, despite disagreements among some. This has led to the theory that oxidative stress resulting from abnormal homeostasis of these transition metals may be a causative explanation behind AD. In the nervous system, the interaction of metals with proteins appears to be an essential variable in the development or suppression of neurodegeneration. Chelation treatment may be an option for treating neurodegeneration induced by transition metal ion dyshomeostasis. Some clinicians even recommend using chelating agents as an adjunct therapy for AD. The current review also looks at the therapeutic strategies that have been attempted, primarily with metal-chelating drugs. Metal buildup in the nervous system, as reported in the AD, could be the result of compensatory mechanisms designed to improve metal availability for physiological functions.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10916-10940"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis. 过亚硝酸盐触发的一氧化碳供体通过抑制神经元凋亡和铁凋亡改善缺血性脑卒中的预后

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-20 DOI: 10.1007/s12035-024-04238-w

Xin-Jian Guo, Lin-Yan Huang, Shi-Tong Gong, Ming Li, Wan Wang, Jie Chen, Yi-De Zhang, Xicun Lu, Xiaohua Chen, Lan Luo, Youjun Yang, Xiao Luo, Su-Hua Qi

{"title":"Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis.","authors":"Xin-Jian Guo, Lin-Yan Huang, Shi-Tong Gong, Ming Li, Wan Wang, Jie Chen, Yi-De Zhang, Xicun Lu, Xiaohua Chen, Lan Luo, Youjun Yang, Xiao Luo, Su-Hua Qi","doi":"10.1007/s12035-024-04238-w","DOIUrl":"10.1007/s12035-024-04238-w","url":null,"abstract":"Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO-). We recently developed a new ONOO--triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO-. ONOO- scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased glutathione peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO- reaction with PCOD585 further inhibited the neuronal Iron-dependent ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10629-10644"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expression of Dystrophin Dp71 Splice Variants Is Temporally Regulated During Rodent Brain Development. 啮齿动物大脑发育过程中 Dystrophin Dp71 突变体的表达受时间调控

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-28 DOI: 10.1007/s12035-024-04232-2

Mayram González-Reyes, Jorge Aragón, Alejandra Sánchez-Trujillo, Griselda Rodríguez-Martínez, Kevin Duarte, Evangelia Eleftheriou, Jean-Vianney Barnier, Delphine Naquin, Claude Thermes, José Romo-Yáñez, Jérome E Roger, Alvaro Rendon, Cyrille Vaillend, Cecilia Montanez

{"title":"Expression of Dystrophin Dp71 Splice Variants Is Temporally Regulated During Rodent Brain Development.","authors":"Mayram González-Reyes, Jorge Aragón, Alejandra Sánchez-Trujillo, Griselda Rodríguez-Martínez, Kevin Duarte, Evangelia Eleftheriou, Jean-Vianney Barnier, Delphine Naquin, Claude Thermes, José Romo-Yáñez, Jérome E Roger, Alvaro Rendon, Cyrille Vaillend, Cecilia Montanez","doi":"10.1007/s12035-024-04232-2","DOIUrl":"10.1007/s12035-024-04232-2","url":null,"abstract":"Dystrophin Dp71 is the major product of the Duchenne muscular dystrophy (DMD) gene in the brain, and its loss in DMD patients and mouse models leads to cognitive impairments. Dp71 is expressed as a range of proteins generated by alternative splicing of exons 71 to 74 and 78, classified in the main Dp71d and Dp71f groups that contain specific C-terminal ends. However, it is unknown whether each isoform has a specific role in distinct cell types, brain regions, and/or stages of brain development. In the present study, we characterized the expression of Dp71 isoforms during fetal (E10.5, E15.5) and postnatal (P1, P7, P14, P21 and P60) mouse and rat brain development. We finely quantified the expression of several Dp71 transcripts by RT-PCR and cloning assays in samples from whole-brain and distinct brain structures. The following Dp71 transcripts were detected: Dp71d, Dp71d∆71, Dp71d∆74, Dp71d∆71,74, Dp71d∆71-74, Dp71f, Dp71f∆71, Dp71f∆74, Dp71f∆71,74, and Dp71fΔ71-74. We found that the Dp71f isoform is the main transcript expressed at E10.5 (> 80%), while its expression is then progressively reduced and replaced by the expression of isoforms of the Dp71d group from E15.5 to postnatal and adult ages. This major finding was confirmed by third-generation nanopore sequencing. In addition, we found that the level of expression of specific Dp71 isoforms varies as a function of postnatal stages and brain structure. Our results suggest that Dp71 isoforms have different and complementary roles during embryonic and postnatal brain development, likely taking part in a variety of maturation processes in distinct cell types.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10883-10900"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

COVID-19, Anxiety, and Body Mass Index Increase Leptin Levels: a Cross-sectional Multicentric Study. COVID-19、焦虑和体重指数会增加瘦素水平：一项横断面多中心研究。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2023-12-20 DOI: 10.1007/s12035-023-03788-9

Gislaine Z Réus, Kelen C C Recco, Karynne M S H Machado, Ritele H Silva, Camila O Arent, Graziela Amboni, Flávia S Niero, Lucas C Pedro, Laura A Borba, Margarete D Bagatini, Gabriela G de Oliveira, Alana Patrícia da Silva, Maiqueli Eduarda D Mingoti, Zuleide Maria Ignácio, Fernanda F Gava, Fabricia Petronilho, João Quevedo, Luciane B Ceretta, Taiane de Azevedo Cardoso

{"title":"COVID-19, Anxiety, and Body Mass Index Increase Leptin Levels: a Cross-sectional Multicentric Study.","authors":"Gislaine Z Réus, Kelen C C Recco, Karynne M S H Machado, Ritele H Silva, Camila O Arent, Graziela Amboni, Flávia S Niero, Lucas C Pedro, Laura A Borba, Margarete D Bagatini, Gabriela G de Oliveira, Alana Patrícia da Silva, Maiqueli Eduarda D Mingoti, Zuleide Maria Ignácio, Fernanda F Gava, Fabricia Petronilho, João Quevedo, Luciane B Ceretta, Taiane de Azevedo Cardoso","doi":"10.1007/s12035-023-03788-9","DOIUrl":"10.1007/s12035-023-03788-9","url":null,"abstract":"Although many efforts have been made to understand the pathophysiological mechanisms of COVID-19, critical gaps remain to be explored. This study aimed to investigate potential alterations in adipokine levels (specifically adiponectin, leptin, and resistin) among individuals with COVID-19. Within this population, we further assessed the association between these markers with both, body mass index (BMI) and psychiatric symptoms. This cross-sectional study included an age- and sex-matched sample of adults with COVID-19 (cases) and without COVID-19 (controls). We evaluated the severity of psychiatric symptoms, BMI, and adipokines. Individuals with COVID-19 presented greater BMI, stress levels, and leptin levels when compared to controls. Leptin levels were greater in individuals with moderate/severe COVID-19 as compared to individuals with COVID-19 who were asymptomatic or having mild symptoms. Leptin levels were positively correlated with BMI, severity of depressive and anxiety symptoms, and stress levels in the total sample. Leptin levels were also positively correlated with BMI, severity of anxiety symptoms, and stress levels in controls. In cases, there was a positive correlation between adiponectin and the severity of depressive symptoms and stress levels and leptin/resistin with BMI. A linear regression model revealed that BMI, severity of anxiety symptoms, and the diagnosis of COVID-19 are independently associated with increased leptin levels. Thus, leptin levels seem to be impacted by the COVID-19 infection, anxiety, and BMI.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10041-10050"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138830524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

What Is the Impact of the Novel Coronavirus and the Vaccination on Guillain-Barre Syndrome? 新型冠状病毒和疫苗接种对格林-巴利综合征有什么影响？

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2023-09-20 DOI: 10.1007/s12035-023-03638-8

Yinuo Chen, Kezheng Li, Wenjing Lv, Jiali Xie, Yuqin Qian, Can Cui, Binbin Deng

引用次数: 0

MSC Promotes the Secretion of Exosomal lncRNA KLF3-AS1 to Regulate Sphk1 Through YY1-Musashi-1 Axis and Improve Cerebral Ischemia-Reperfusion Injury. 间充质干细胞通过YY1-Musashi-1轴促进外泌体lncRNA KLF3-AS1的分泌以调控Sphk1并改善脑缺血再灌注损伤

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-13 DOI: 10.1007/s12035-024-04150-3

Yu Cao, Daodao Wang, Dingzhou Zhou

{"title":"MSC Promotes the Secretion of Exosomal lncRNA KLF3-AS1 to Regulate Sphk1 Through YY1-Musashi-1 Axis and Improve Cerebral Ischemia-Reperfusion Injury.","authors":"Yu Cao, Daodao Wang, Dingzhou Zhou","doi":"10.1007/s12035-024-04150-3","DOIUrl":"10.1007/s12035-024-04150-3","url":null,"abstract":"Stroke remains the 3rd leading cause of long-term disability globally. Over the past decade, mesenchymal stem cell (MSC) transplantation has been proven as an effective therapy for ischemic stroke. However, the mechanism of MSC-derived exosomal lncRNAs during cerebral ischemia/reperfusion (I/R) remains ambiguous. The oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO) rat model were generated. MSCs were isolated and characterized by flow cytometry and histochemical staining, and MSC exosomes were purified and characterized by transmission electron microscopy, flow cytometry and Western blot. Western blot, RT-qPCR and ELISA assay were employed to examine the expression or secretion of key molecules. CCK-8 and TUNEL assays were used to assess cell viability and apoptosis. RNA immunoprecipitation and RNA pull-down were used to investigate the direct association between krüppel-like factor 3 antisense RNA 1 (KLF3-AS1) and musashi-1(MSI1). Yin Yang 1 (YY1)-mediated transcriptional regulation was assessed by chromatin immunoprecipitation and luciferase assays. The histological changes and immunoreactivity of key molecules in brain tissues were examined by H&E and immunohistochemistry. MSCs were successfully isolated and exhibited directionally differential potentials. MSC exosomal KLF3-AS1 alleviated OGD/R-induced inflammation in SK-N-SH and SH-SY5Y cells via modulating Sphk1. Mechanistical studies showed that MSI1 positively regulated KLF3-AS1 expression through its direct binding to KLF3-AS1. YY1 was identified as a transcription activator of MSI1 in MSCs. Functionally, YY1/MSI1 axis regulated the release of MSC exosomal KLF3-AS1 to modulate sphingosine kinase 1 (Sphk1)/NF-κB pathway, thereby ameliorating OGD/R- or cerebral I/R-induced injury. MSCs promote the release of exosomal KLF3-AS1 to regulate Sphk1 through YY1/MSI axis and improve cerebral I/R injury.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10462-10480"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study. T细胞特征的循环水平与肌萎缩侧索硬化症的风险：孟德尔随机研究》。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-15 DOI: 10.1007/s12035-024-04226-0

Ting Lu, Lijun Luo, Jie Yang, Xiao Cheng, Jingbo Sun

{"title":"Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.","authors":"Ting Lu, Lijun Luo, Jie Yang, Xiao Cheng, Jingbo Sun","doi":"10.1007/s12035-024-04226-0","DOIUrl":"10.1007/s12035-024-04226-0","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10529-10537"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Mitochondrial Protein TAMM41 Modulates Depressive-like Behaviors. 线粒体蛋白质 TAMM41 调节抑郁样行为

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-16 DOI: 10.1007/s12035-024-04233-1

Lin Guo, Ziyu Liu, Xiaoxia Jia, Qinghua Wang, Jianlun Ji, Na Lv, Zhidong Liu, Qin Zhou, Congcong Sun, Yun Wang

{"title":"Mitochondrial Protein TAMM41 Modulates Depressive-like Behaviors.","authors":"Lin Guo, Ziyu Liu, Xiaoxia Jia, Qinghua Wang, Jianlun Ji, Na Lv, Zhidong Liu, Qin Zhou, Congcong Sun, Yun Wang","doi":"10.1007/s12035-024-04233-1","DOIUrl":"10.1007/s12035-024-04233-1","url":null,"abstract":"Several lines of evidence have highlighted the crucial role of mitochondria-based therapy in depression. However, there are still less mitochondrial targets for the depression treatment. TAM41 mitochondrial translocator assembly and maintenance homolog (TAMM41) is a mitochondrial inner membrane protein for maintaining mitochondrial function, which is tightly related to many brain diseases including Alzheimer's diseases and epilepsy. Here, we investigated whether TAMM41 would be a potential target to treat depression. We found that the expression of TAMM41 was markedly lower in corticosterone-induced depression, lipopolysaccharide-induced depression, and depressed patients. Meanwhile, loss of TAMM41 resulted in increased immobility in the forced swim test (FST), tail suspension test (TST), and center time in open field test (OFT), suggesting depressive-like behaviors in mice. Moreover, genetic overexpression of TAMM41 obviously exerted antidepressant-like activities. Mechanistically, proteomics revealed that pacsin1 might be the underlying target of TAMM41. Further data supported that TAMM41 regulated the expression of pacsin1, and its antidepressant-like effect at least partially was attributed to pacsin1. In addition, exosomes containing TAMM41 was sufficient to exhibit antidepressant-like effect, suggesting an alternative strategy to exert the effect of TAMM41. Taken together, the present study demonstrates the antidepressant-like effect of TAMM41 and sheds light on its molecular mechanism. These finding provide new insights into a therapeutic strategy targeting mitochondria in the development of novel antidepressants.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10561-10573"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

METTL14/YTHDC1-Mediated m6A Modification in Hippocampus Improves Pentylenetetrazol-Induced Acute Seizures. 海马中由 METTL14/YTHDC1 介导的 m6A 修饰可改善戊四唑诱导的急性癫痫发作。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-30 DOI: 10.1007/s12035-024-04252-y

Xiaolin Zhong, Ling Chen, Yajuan Wang, Yue Liang, Yanmei Huang, Zuyao Chen, Wenyu Cao, Jianghua Liu, Xuyu Zu

{"title":"METTL14/YTHDC1-Mediated m6A Modification in Hippocampus Improves Pentylenetetrazol-Induced Acute Seizures.","authors":"Xiaolin Zhong, Ling Chen, Yajuan Wang, Yue Liang, Yanmei Huang, Zuyao Chen, Wenyu Cao, Jianghua Liu, Xuyu Zu","doi":"10.1007/s12035-024-04252-y","DOIUrl":"10.1007/s12035-024-04252-y","url":null,"abstract":"Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined significantly in the dentate gyrus (DG) of hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of DG area neuron were significantly mitigated after the administration of m6A agonist betaine. Mechanically, we found that both the m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased by PTZ stimulation, which might contribute to the reduced m6A level. Additionally, DG-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized m6A level. Together, this study identified that METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10979-10991"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Role of PIM Kinase Inhibitor in the Treatment of Alzheimer's Disease. PIM 激酶抑制剂在治疗阿尔茨海默病中的作用。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2024-12-01 Epub Date: 2024-05-30 DOI: 10.1007/s12035-024-04257-7

Shreyasi Meur, Swarupananda Mukherjee, Souvik Roy, Dipanjan Karati

{"title":"Role of PIM Kinase Inhibitor in the Treatment of Alzheimer's Disease.","authors":"Shreyasi Meur, Swarupananda Mukherjee, Souvik Roy, Dipanjan Karati","doi":"10.1007/s12035-024-04257-7","DOIUrl":"10.1007/s12035-024-04257-7","url":null,"abstract":"Alzheimer's disease (AD), a neurodegenerative disorder, is the most prevalent form of senile dementia, causing progressive deterioration of cognition, behavior, and rational skills. Neuropathologically, AD is characterized by two hallmark proteinaceous aggregates: amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) formed of hyperphosphorylated tau. A significant study has been done to understand how Aβ and/or tau accumulation can alter signaling pathways that affect neuronal function. A conserved protein kinase known as the mammalian target of rapamycin (mTOR) is essential for maintaining the proper balance between protein synthesis and degradation. Overwhelming evidence shows mTOR signaling's primary role in age-dependent cognitive decline and the pathogenesis of AD. Postmortem human AD brains consistently show an upregulation of mTOR signaling. Confocal microscopy findings demonstrated a direct connection between mTOR and intraneuronal Aβ42 through molecular processes of PRAS40 phosphorylation. By attaching to the mTORC1 complex, PRAS40 inhibits the activity of mTOR. Furthermore, inhibiting PRAS40 phosphorylation can stop the Aβ-mediated increase in mTOR activity, indicating that the accumulation of Aβ may aid in PRAS40 phosphorylation. Physiologically, PRAS40 is phosphorylated by PIM1 which is a serine/threonine kinase of proto-oncogene PIM kinase family. Pharmacological inhibition of PIM1 activity prevents the Aβ-induced mTOR hyperactivity in vivo by blocking PRAS40 phosphorylation and restores cognitive impairments by enhancing proteasome function. Recently identified small-molecule PIM1 inhibitors have been developed as potential therapeutic to reduce AD-neuropathology. This comprehensive study aims to address the activity of PIM1 inhibitor that has been tested for the treatment of AD, in addition to the pharmacological and structural aspects of PIM1.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"10941-10955"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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