Introduction: Genetic studies have shown that variants in the microtubule-associated protein tau (MAPT) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the MAPT gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of MAPT haplotypes (H1 and H2) and MAPT haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD.
Methods: The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls.
Results: The results showed that individuals carrying the A allele in the MAPT rs1467967 polymorphism, the GG genotype in the MAPT rs7521 polymorphism, and the G allele in the MAPT rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in MAPT rs2471738 polymorphism and CC homozygotes also showed worse performance on neuropsychological tests and pathological levels of several cerebrospinal fluid (CSF) biomarkers. However, T allele carriers in the MAPT rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E (APOE) ɛ4 carriers. Carriers of the H2 MAPT haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 MAPT haplotype with pathological levels of CSF AD biomarkers. Regarding the MAPT rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers.
Discussion: In conclusion, further genetic studies are needed to elucidate the role of MAPT haplotypes and MAPT haplotype-tagging polymorphisms in the development of AD.
简介遗传学研究表明，编码 tau 蛋白的微管相关蛋白 tau（MAPT）基因的变异可增加阿尔茨海默病（AD）的患病风险。此外，MAPT 基因的两种单倍型（H1 和 H2）与包括阿尔茨海默病在内的多种神经退行性疾病有关。本研究旨在检测 MAPT 单倍型（H1 和 H2）和 MAPT 单倍型标记多态性（rs1467967、rs242557、rs3785883、rs2471738、del-In9、rs7521）与 AD 的相关性：研究纳入了 964 人：方法：研究对象包括 964 人：113 名 AD 患者、53 名轻度认知障碍患者 (MCI)、54 名其他痴呆症患者和 744 名健康对照组：结果显示，MAPT rs1467967 多态性中的 A 等位基因、MAPT rs7521 多态性中的 GG 基因型和 MAPT rs242557 多态性中的 G 等位基因携带者在各种神经心理测试中的表现较差。MAPT rs2471738 多态性的 C 等位基因携带者和 CC 同卵双生者在神经心理测试中的表现也较差，几种脑脊液（CSF）生物标志物的病理水平也较低。然而，MAPT rs2471738 多态性的 T 等位基因携带者在痴呆症患者和载脂蛋白 E（APOE）ɛ4 携带者中的比例更高。H2 MAPT单倍型携带者在各种神经心理测试中的表现较差，这与我们之前的研究一致，该研究将H2 MAPT单倍型与CSF AD生物标志物的病理水平相关联。关于MAPT rs3785883多态性，由于AA和GG基因型均与CSF和血浆AD生物标志物的病理水平相关，因此还需要进一步研究：总之，要阐明MAPT单倍型和MAPT单倍型标记多态性在AD发病中的作用，还需要进一步的遗传学研究。
{"title":"Further validation of the association between <i>MAPT</i> haplotype-tagging polymorphisms and Alzheimer's disease: neuropsychological tests, cerebrospinal fluid biomarkers, and <i>APOE</i> genotype.","authors":"Mirjana Babić Leko, Ena Španić Popovački, Nanet Willumsen, Matea Nikolac Perković, Nikolina Pleić, Klara Zubčić, Lea Langer Horvat, Željka Vogrinc, Marina Boban, Fran Borovečki, Tatijana Zemunik, Rohan de Silva, Goran Šimić","doi":"10.3389/fnmol.2024.1456670","DOIUrl":"10.3389/fnmol.2024.1456670","url":null,"abstract":"<p><strong>Introduction: </strong>Genetic studies have shown that variants in the microtubule-associated protein tau (<i>MAPT</i>) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the <i>MAPT</i> gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of <i>MAPT</i> haplotypes (H1 and H2) and <i>MAPT</i> haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD.</p><p><strong>Methods: </strong>The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls.</p><p><strong>Results: </strong>The results showed that individuals carrying the A allele in the <i>MAPT</i> rs1467967 polymorphism, the GG genotype in the <i>MAPT</i> rs7521 polymorphism, and the G allele in the <i>MAPT</i> rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in <i>MAPT</i> rs2471738 polymorphism and CC homozygotes also showed worse performance on neuropsychological tests and pathological levels of several cerebrospinal fluid (CSF) biomarkers. However, T allele carriers in the <i>MAPT</i> rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E (<i>APOE</i>) ɛ4 carriers. Carriers of the H2 <i>MAPT</i> haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 <i>MAPT</i> haplotype with pathological levels of CSF AD biomarkers. Regarding the <i>MAPT</i> rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers.</p><p><strong>Discussion: </strong>In conclusion, further genetic studies are needed to elucidate the role of <i>MAPT</i> haplotypes and <i>MAPT</i> haplotype-tagging polymorphisms in the development of AD.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1456670"},"PeriodicalIF":3.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although salt is an essential substance vital to life, excessive salt intake could cause various health issues. Therefore, new technologies and strategies should be developed to reduce salt intake without compromising taste. However, the underlying physiological mechanisms of salt taste reception is complex and not completely understood. Sodium chloride is a typical salty substance. It is widely believed that only sodium is important for the generation of salty taste. On the other hand, from a psychophysical perspective, the importance of chloride in salty taste has been indicated. Thus, understanding the mechanisms of both sodium- and chloride-tastes generation is necessary to completely comprehended the fundamentals of salt taste reception. However, the mechanism for detecting chloride taste has remained unclear for many years. Recently, we have identified transmembrane channel-like 4 (TMC4) as the first molecule that mediates the reception of chloride taste. TMC4 functions as a voltage-dependent chloride channel and plays an important role in the reception of the chloride taste by detecting chloride ions. In this mini-review, we first introduce the known reception mechanism of salty taste, and then discuss the roles of TMC4 in the salt taste reception. The finding of TMC4 may serve as a basis for developing new technologies and formulating strategies to reduce salt intake without compromising taste.
{"title":"The complexities of salt taste reception: insights into the role of TMC4 in chloride taste detection.","authors":"Yoichi Kasahara, Masataka Narukawa, Yoshikazu Saito, Keiko Abe, Tomiko Asakura","doi":"10.3389/fnmol.2024.1468438","DOIUrl":"10.3389/fnmol.2024.1468438","url":null,"abstract":"<p><p>Although salt is an essential substance vital to life, excessive salt intake could cause various health issues. Therefore, new technologies and strategies should be developed to reduce salt intake without compromising taste. However, the underlying physiological mechanisms of salt taste reception is complex and not completely understood. Sodium chloride is a typical salty substance. It is widely believed that only sodium is important for the generation of salty taste. On the other hand, from a psychophysical perspective, the importance of chloride in salty taste has been indicated. Thus, understanding the mechanisms of both sodium- and chloride-tastes generation is necessary to completely comprehended the fundamentals of salt taste reception. However, the mechanism for detecting chloride taste has remained unclear for many years. Recently, we have identified transmembrane channel-like 4 (TMC4) as the first molecule that mediates the reception of chloride taste. TMC4 functions as a voltage-dependent chloride channel and plays an important role in the reception of the chloride taste by detecting chloride ions. In this mini-review, we first introduce the known reception mechanism of salty taste, and then discuss the roles of TMC4 in the salt taste reception. The finding of TMC4 may serve as a basis for developing new technologies and formulating strategies to reduce salt intake without compromising taste.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1468438"},"PeriodicalIF":3.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fnmol.2024.1397378
Richard Taylor, Nikolas Nikolaou
In neurons, a diverse range of coding and non-coding RNAs localize to axons, dendrites, and synapses, where they facilitate rapid responses to local needs, such as axon and dendrite extension and branching, synapse formation, and synaptic plasticity. Here, we review the extent of our current understanding of RNA subclass diversity in these functionally demanding subcellular compartments. We discuss the similarities and differences identified between axonal, dendritic and synaptic local transcriptomes, and discuss the reported and hypothesized fates and functions of localized RNAs. Furthermore, we outline the RNA composition of exosomes that bud off from neurites, and their implications for the biology of neighboring cells. Finally, we highlight recent advances in third-generation sequencing technologies that will likely provide transformative insights into splice isoform and RNA modification diversity in local transcriptomes.
{"title":"RNA in axons, dendrites, synapses and beyond","authors":"Richard Taylor, Nikolas Nikolaou","doi":"10.3389/fnmol.2024.1397378","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1397378","url":null,"abstract":"In neurons, a diverse range of coding and non-coding RNAs localize to axons, dendrites, and synapses, where they facilitate rapid responses to local needs, such as axon and dendrite extension and branching, synapse formation, and synaptic plasticity. Here, we review the extent of our current understanding of RNA subclass diversity in these functionally demanding subcellular compartments. We discuss the similarities and differences identified between axonal, dendritic and synaptic local transcriptomes, and discuss the reported and hypothesized fates and functions of localized RNAs. Furthermore, we outline the RNA composition of exosomes that bud off from neurites, and their implications for the biology of neighboring cells. Finally, we highlight recent advances in third-generation sequencing technologies that will likely provide transformative insights into splice isoform and RNA modification diversity in local transcriptomes.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"27 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249303","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}
Pub Date : 2024-09-18DOI: 10.3389/fnmol.2024.1462769
Shirelle X. Liu, Andrew C. Harris, Jonathan C. Gewirtz
Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap.
药物滥用障碍（SUD）是一个巨大且日益严重的全球性健康问题。尽管滥用药物具有很强的成瘾性，但只有少数接触者会发展成 SUD。虽然某些生活经历（如童年创伤）可能会增加日后患上药物滥用障碍的可能性，但这些影响的内在机制尚不十分清楚。鉴于药物依赖性失调症的慢性和复发性，以及先前的生活事件和随后的药物接触之间可能间隔的时间长度，药物依赖性失调症易感性的变化几乎肯定涉及长期的表观遗传失调。为了验证这一观点，我们在多种 SUDs 动物模型中研究了特定表观遗传修饰对介导强化学习的脑区（如伏隔核、前额叶皮层）的功能影响。此外，人们还研究了先前的生活经历所产生的表观遗传修饰对随后的药物依赖性易感性的影响，但大多是以相关的方式进行的。在此，我们回顾了表观遗传机制如何影响动物模型中与 SUD 相关的行为，并总结了我们对生活经历、表观遗传调控和未来易患 SUD 之间关系的理解。尽管研究设计存在差异，但对 SUD 相关行为产生最一致影响的表观遗传修饰主要是那些对基因调控产生单向影响的修饰，如 DNA 甲基化和组蛋白磷酸化。将环境诱导的表观遗传修饰与随后的 SUD 相关行为明确联系起来的证据少得令人吃惊。最后，我们提出了未来研究的几个方向，以着手解决这一关键的研究空白。
{"title":"How life events may confer vulnerability to addiction: the role of epigenetics","authors":"Shirelle X. Liu, Andrew C. Harris, Jonathan C. Gewirtz","doi":"10.3389/fnmol.2024.1462769","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1462769","url":null,"abstract":"Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"38 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249263","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}
Pub Date : 2024-09-18DOI: 10.3389/fnmol.2024.1406708
Kai Xin Li, Lei Fan, Hongjuan Wang, Yushan Tian, Sen Zhang, Qingyuan Hu, Fanglin Liu, Huan Chen, Hongwei Hou
The Monoamine Oxidase-A (MAOA) EcoRV polymorphism (rs1137070) is a unique synonymous mutation (c.1409 T > C) within the MAOA gene, which plays a crucial role in Maoa gene expression and function. This study aimed to explore the relationship between the mouse Maoa rs1137070 genotype and differences in MAOA gene expression. Mice carrying the CC genotype of rs1137070 exhibited a significantly lower Maoa expression level, with an odds ratio of 2.44 compared to the T carriers. Moreover, the wild-type TT genotype of MAOA demonstrated elevated mRNA expression and a longer half-life. We also delved into the significant expression and structural disparities among genotypes. Furthermore, it was evident that different aspartic acid synonymous codons within Maoa influenced both MAOA expression and enzyme activity, highlighting the association between rs1137070 and MAOA. To substantiate these findings, a dual-luciferase reporter assay confirmed that GAC was more efficient than GAT binding. Conversely, the synonymous mutation altered Maoa gene expression in individual mice. An RNA pull-down assay suggested that this alteration could impact the interaction with RNA-binding proteins. In summary, our results illustrate that synonymous mutations can indeed regulate the downregulation of gene expression, leading to changes in MAOA function and their potential association with neurological-related diseases.
{"title":"A synonymous mutation of rs1137070 cause the mice Maoa gene transcription and translation to decrease","authors":"Kai Xin Li, Lei Fan, Hongjuan Wang, Yushan Tian, Sen Zhang, Qingyuan Hu, Fanglin Liu, Huan Chen, Hongwei Hou","doi":"10.3389/fnmol.2024.1406708","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1406708","url":null,"abstract":"The Monoamine Oxidase-A (<jats:italic>MAOA</jats:italic>) EcoRV polymorphism (rs1137070) is a unique synonymous mutation (c.1409 T &gt; C) within the <jats:italic>MAOA</jats:italic> gene, which plays a crucial role in <jats:italic>Maoa</jats:italic> gene expression and function. This study aimed to explore the relationship between the mouse <jats:italic>Maoa</jats:italic> rs1137070 genotype and differences in <jats:italic>MAOA</jats:italic> gene expression. Mice carrying the CC genotype of rs1137070 exhibited a significantly lower <jats:italic>Maoa</jats:italic> expression level, with an odds ratio of 2.44 compared to the T carriers. Moreover, the wild-type TT genotype of MAOA demonstrated elevated mRNA expression and a longer half-life. We also delved into the significant expression and structural disparities among genotypes. Furthermore, it was evident that different aspartic acid synonymous codons within <jats:italic>Maoa</jats:italic> influenced both <jats:italic>MAOA</jats:italic> expression and enzyme activity, highlighting the association between rs1137070 and MAOA. To substantiate these findings, a dual-luciferase reporter assay confirmed that GAC was more efficient than GAT binding. Conversely, the synonymous mutation altered <jats:italic>Maoa</jats:italic> gene expression in individual mice. An RNA pull-down assay suggested that this alteration could impact the interaction with RNA-binding proteins. In summary, our results illustrate that synonymous mutations can indeed regulate the downregulation of gene expression, leading to changes in MAOA function and their potential association with neurological-related diseases.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"233 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249264","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}
Pub Date : 2024-09-18DOI: 10.3389/fnmol.2024.1473058
Miriana Scordino, Polina Stepanova, Vignesh Srinivasan, Dan Duc Pham, Ove Eriksson, Maciej Lalowski, Giuseppa Mudò, Valentina Di Liberto, Laura Korhonen, Merja H. Voutilainen, Dan Lindholm
Canopy Homolog 2 (CNPY2) is an endoplasmic reticulum (ER) localized protein belonging to the CNPY gene family. We show here that CNPY2 is protective against ER stress induced by tunicamycin in neuronal cells. Overexpression of CNPY2 enhanced, while downregulation of CNPY2 using shRNA expression, reduced the viability of neuroblastoma cells after tunicamycin. Likewise, recombinant CNPY2 increased survival of cortical neurons in culture after ER stress. CNPY2 reduced the activating transcription factor 6 (ATF6) branch of ER stress and decreased the expression of CCAT/Enhancer-Binding Protein Homologous Protein (CHOP) involved in cell death. Immunostaining using mouse brain sections revealed that CNPY2 is expressed by cortical and striatal neurons and is co-expressed with the transcription factor, COUPTF-interacting protein 2 (CTIP2). In transgenic N171-82Q mice, as a model for Huntington’s disease (HD), the number of CNPY2-immunopositive neurons was increased in the cortex together with CTIP2. In the striatum, however, the number of CNPY2 decreased at 19 weeks of age, representing a late-stage of pathology. Striatal cells in culture were shown to be more susceptible to ER stress after downregulation of CNPY2. These results demonstrate that CNPY2 is expressed by corticostriatal neurons involved in the regulation of movement. CNPY2 enhances neuronal survival by reducing ER stress and is a promising factor to consider in HD and possibly in other brain diseases.
{"title":"CNPY2 protects against ER stress and is expressed by corticostriatal neurons together with CTIP2 in a mouse model of Huntington’s disease","authors":"Miriana Scordino, Polina Stepanova, Vignesh Srinivasan, Dan Duc Pham, Ove Eriksson, Maciej Lalowski, Giuseppa Mudò, Valentina Di Liberto, Laura Korhonen, Merja H. Voutilainen, Dan Lindholm","doi":"10.3389/fnmol.2024.1473058","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1473058","url":null,"abstract":"Canopy Homolog 2 (CNPY2) is an endoplasmic reticulum (ER) localized protein belonging to the CNPY gene family. We show here that CNPY2 is protective against ER stress induced by tunicamycin in neuronal cells. Overexpression of CNPY2 enhanced, while downregulation of CNPY2 using shRNA expression, reduced the viability of neuroblastoma cells after tunicamycin. Likewise, recombinant CNPY2 increased survival of cortical neurons in culture after ER stress. CNPY2 reduced the activating transcription factor 6 (ATF6) branch of ER stress and decreased the expression of CCAT/Enhancer-Binding Protein Homologous Protein (CHOP) involved in cell death. Immunostaining using mouse brain sections revealed that CNPY2 is expressed by cortical and striatal neurons and is co-expressed with the transcription factor, COUPTF-interacting protein 2 (CTIP2). In transgenic N171-82Q mice, as a model for Huntington’s disease (HD), the number of CNPY2-immunopositive neurons was increased in the cortex together with CTIP2. In the striatum, however, the number of CNPY2 decreased at 19 weeks of age, representing a late-stage of pathology. Striatal cells in culture were shown to be more susceptible to ER stress after downregulation of CNPY2. These results demonstrate that CNPY2 is expressed by corticostriatal neurons involved in the regulation of movement. CNPY2 enhances neuronal survival by reducing ER stress and is a promising factor to consider in HD and possibly in other brain diseases.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"171 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249302","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}
Pub Date : 2024-09-16eCollection Date: 2024-01-01DOI: 10.3389/fnmol.2024.1487141
Mario A Acuña, Kristina Valentinova, Pascal Darbon
{"title":"Editorial: Molecular neurobiology of chronic pain: pharmacological and non-pharmacological approaches in animal models.","authors":"Mario A Acuña, Kristina Valentinova, Pascal Darbon","doi":"10.3389/fnmol.2024.1487141","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1487141","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1487141"},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Every-other-day fasting (EODF) is a form of caloric restriction that alternates between periods of normal eating and fasting, aimed at preventing and treating diseases. This approach has gained widespread usage in basic research on neurological conditions, including spinal cord injury, and has demonstrated significant neuroprotective effects. Additionally, EODF is noted for its safety and feasibility, suggesting broad potential for application. This study aims to evaluate the therapeutic effects of EODF on spinal cord injury and to investigate and enhance its underlying mechanisms. Initially, the SCI rat model was utilized to evaluate the effects of EODF on pathological injury and motor function. Subsequently, considering the enhancement of metabolism through EODF, bile acid metabolism in SCI rats was analyzed using liquid chromatography-mass spectrometry (LC–MS), and the expression of the bile acid receptor TGR5 was further assessed. Ultimately, it was confirmed that EODF influences the activation of microglia and NLRP3 inflammasomes associated with the TGR5 signaling, along with the expression of downstream pyroptosis pathway related proteins and inflammatory cytokines, as evidenced by the activation of the NLRP3/Caspase-1/GSDMD pyroptosis pathway in SCI rats. The results demonstrated that EODF significantly enhanced the recovery of motor function and reduced pathological damage in SCI rats while controlling weight gain. Notably, EODF promoted the secretion of bile acid metabolites, activated TGR5, and inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway and inflammation in these rats. In summary, EODF could mitigate secondary injury after SCI and foster functional recovery by improving metabolism, activating the TGR5 signaling and inhibiting the NLRP3 pyroptosis pathway.
{"title":"Every-other-day fasting inhibits pyroptosis while regulating bile acid metabolism and activating TGR5 signaling in spinal cord injury","authors":"Honghu Song, Rizhao Pang, Zhixuan Chen, Linjie Wang, Xiaomin Hu, Jingzhi Feng, Wenchun Wang, Jiancheng Liu, Anren Zhang","doi":"10.3389/fnmol.2024.1466125","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1466125","url":null,"abstract":"Every-other-day fasting (EODF) is a form of caloric restriction that alternates between periods of normal eating and fasting, aimed at preventing and treating diseases. This approach has gained widespread usage in basic research on neurological conditions, including spinal cord injury, and has demonstrated significant neuroprotective effects. Additionally, EODF is noted for its safety and feasibility, suggesting broad potential for application. This study aims to evaluate the therapeutic effects of EODF on spinal cord injury and to investigate and enhance its underlying mechanisms. Initially, the SCI rat model was utilized to evaluate the effects of EODF on pathological injury and motor function. Subsequently, considering the enhancement of metabolism through EODF, bile acid metabolism in SCI rats was analyzed using liquid chromatography-mass spectrometry (LC–MS), and the expression of the bile acid receptor TGR5 was further assessed. Ultimately, it was confirmed that EODF influences the activation of microglia and NLRP3 inflammasomes associated with the TGR5 signaling, along with the expression of downstream pyroptosis pathway related proteins and inflammatory cytokines, as evidenced by the activation of the NLRP3/Caspase-1/GSDMD pyroptosis pathway in SCI rats. The results demonstrated that EODF significantly enhanced the recovery of motor function and reduced pathological damage in SCI rats while controlling weight gain. Notably, EODF promoted the secretion of bile acid metabolites, activated TGR5, and inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway and inflammation in these rats. In summary, EODF could mitigate secondary injury after SCI and foster functional recovery by improving metabolism, activating the TGR5 signaling and inhibiting the NLRP3 pyroptosis pathway.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"4 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215511","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}
Pub Date : 2024-09-11DOI: 10.3389/fnmol.2024.1441691
Hannah Zuppe, Erin Reed
Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer’s Disease (AD) contributes to approximately 60–70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brain-resident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor γ chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics.
痴呆症是描述认知功能退化的总称。它是全球第七大死亡原因，也是导致老年人依赖他人的主要原因之一。阿尔茨海默病（AD）约占痴呆症病例的 60-70%，其特征是淀粉样蛋白斑块和 tau 结在大脑中的积累。神经炎症现已被广泛认为是另一种疾病特征，在疾病的反应和持续过程中都发挥着作用。小胶质细胞是驻留在大脑中的免疫细胞，最初能有效清除淀粉样蛋白斑块，但随着疾病的发展，它们会加剧大脑中的破坏性炎症环境。循环中的外周免疫细胞通过分泌细胞因子促进这种炎症环境，与小胶质细胞形成正反馈循环。这些作用于小胶质细胞的外周衍生细胞因子中有一类是常见的细胞因子受体γ链家族。这些细胞因子与异源二聚体受体结合，激活三种主要信号通路：MAPK、PI3K 和 JAK/STAT。本视角将探讨这三种途径在小胶质细胞中的作用机制，并重点介绍这一研究的未来方向和潜在疗法。
{"title":"Common cytokine receptor gamma chain family cytokines activate MAPK, PI3K, and JAK/STAT pathways in microglia to influence Alzheimer’s Disease","authors":"Hannah Zuppe, Erin Reed","doi":"10.3389/fnmol.2024.1441691","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1441691","url":null,"abstract":"Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer’s Disease (AD) contributes to approximately 60–70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brain-resident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor γ chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"13 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215477","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}
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