Journal of Neurochemistry最新文献

{"title":"Histamine Dynamics During Ingestive Behavior Measured by the Novel Biosensor HisLightG","authors":"K. L. Volcko,&nbsp;A. Gresch,&nbsp;B. Benowitz,&nbsp;H. Taghipourbibalan,&nbsp;M. Visser,&nbsp;V. Rohner,&nbsp;G. D. Stuber,&nbsp;A. G. Gordon-Fennell,&nbsp;T. Patriarchi,&nbsp;J. E. McCutcheon","doi":"10.1111/jnc.70142","DOIUrl":"https://doi.org/10.1111/jnc.70142","url":null,"abstract":"<p>The neurotransmitter histamine is involved in control of food intake, yet its dynamics during individual feeding episodes remain unexplored. Therefore, we used the novel genetically-encoded histamine sensor, HisLightG, combined with fiber photometry to measure histamine release in two hypothalamic regions critical for the food-suppressive effects of histamine, the paraventricular nucleus of the hypothalamus (PVH), and the ventromedial hypothalamus (VMH). Male mice were tested under different conditions to assess whether hunger, time of day, or the caloric content of the solution they were given affected histamine fluctuations. We found that histamine levels changed rapidly in response to eating. These histamine fluctuations were influenced by experimental conditions, with slightly smaller responses when the test solution was sucralose (both regions) or during the light cycle (PVH only). Notable regional differences were identified, such that in the PVH histamine rebounded to above baseline levels, whereas in the VMH histamine remained lower than baseline for at least 10 s after licking ceased. In a separate cohort of male and female mice, enhancing histamine tone via administration of a histamine precursor (L-histidine) reduced the number of licks across multiple sucrose concentrations. Together, these findings indicate that histaminergic activity is modulated rapidly during ingestive episodes, and that understanding these release patterns will give insight into histamine's role in appetite suppression.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551252","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}

{"title":"Plasma Lipidomic Profiles Investigating the Effects of Combined Therapy With Quetiapine and Magnesium Valproate in Emerging Adults With Bipolar II Disorder During Depressive Episodes: A Follow-Up Study","authors":"Yanhua Chen,&nbsp;Yan Yao,&nbsp;Chujun Wu,&nbsp;Hui Li,&nbsp;Manxue Zhang,&nbsp;Zhengwu Peng","doi":"10.1111/jnc.70143","DOIUrl":"https://doi.org/10.1111/jnc.70143","url":null,"abstract":"<div>\u0000 \u0000 <p>Bipolar disorder (BD) is associated with alterations in plasma lipid profiles, which may contribute to its pathogenesis. However, the detailed plasma lipidomic composition of bipolar II disorder during depressive episodes (BPD-II) remains underexplored. This study investigates the temporal changes in plasma lipidomics in BPD-II patients at emerging adulthood undergoing treatment with quetiapine combined with magnesium valproate. We conducted a follow-up study involving individuals with BPD-II at emerging adulthood at baseline (BD-BL, <i>n</i> = 30), 3 weeks (BD-3w, <i>n</i> = 30), and 8 weeks (BD-8w, <i>n</i> = 30) after treatment initiation, as well as gender- and age-matched healthy controls (HC, <i>n</i> = 30). Plasma lipidomics were analyzed using a comprehensive lipidomic profiling approach to identify potential biomarkers. Significant differences in plasma lipid composition were observed between BPD-II patients and healthy controls. Treatment with quetiapine combined with magnesium valproate alleviated symptoms in a time-dependent manner, although residual symptoms persisted after 8 weeks. We identified 64 lipid species with diagnostic potential to distinguish BPD-II from HC and 42 lipid species that could predict treatment outcomes with high reliability. Our findings provide valuable insights into the therapeutic effects of quetiapine combined with magnesium valproate and highlight the potential role of plasma lipidomics in understanding the pathophysiology of BPD-II at emerging adulthood.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551191","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}

{"title":"Milestone Review: The History of Molecular Genetics Analysis of Alzheimer's Disease","authors":"John Hardy","doi":"10.1111/jnc.70148","DOIUrl":"https://doi.org/10.1111/jnc.70148","url":null,"abstract":"<p>Alzheimer research has been driven by genetic findings: from the 1990s until about 2005, by the identification of amyloid precursor protein (<i>APP</i>) and presenilin (<i>PSEN</i>) mutations, leading to the formulation of the amyloid hypothesis, and then from ~2007 by genome-wide studies which have led to the increasing appreciation of the importance of microglial insufficiency in the disease pathogenesis. These genome findings have led not only to key mechanistic insights but also to progress in the use of genetic data to predict those at high risk of the disease so that earlier treatment becomes more practical. In this review I will outline these developments and attempts to synthesise the findings into a coherent single view of the disease.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524690","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}

{"title":"Equivalence of Plasma and Serum for Clinical Measurement of p-tau217: Comparative Analyses of Four Blood-Based Assays","authors":"Yijun Chen,&nbsp;Ally L. Albert,&nbsp;Anuradha Sehrawat,&nbsp;Marissa F. Farinas,&nbsp;Oscar L. Lopez,&nbsp;Xuemei Zeng,&nbsp;Ann D. Cohen,&nbsp;Thomas K. Karikari","doi":"10.1111/jnc.70114","DOIUrl":"https://doi.org/10.1111/jnc.70114","url":null,"abstract":"<p>Phosphorylated tau (p-tau) 217 is a promising blood biomarker for Alzheimer's disease (AD). However, most p-tau217 assays have been validated solely in ethylenediaminetetraacetic acid (EDTA) plasma, leaving the clinical applicability of serum p-tau217 largely unexplored despite serum being a preferred matrix in many clinical laboratories. To address this gap, we compared p-tau217 concentrations and classification accuracies in matched plasma and serum samples in four research-use-only assays. Paired plasma and serum samples were processed from the same venipuncture collection and assessed with each of the four p-tau217 assays following manufacturer-recommended procedures in two research cohorts from the University of Pittsburgh Azheimer's Disease Research Center (Pitt-ADRC; <i>n</i> = 50) and the Human Connectome Project (<i>n</i> = 34). The four assays evaluated included three from commercial sources—Lumipulse (recently gained FDA approval), ALZpath, and NULISA—and another from the University of Pittsburgh (Pittsburgh plasma p-tau217). Plasma and serum p-tau217 levels varied across assays; the ALZpath, Pittsburgh, and NULISA methods showed significantly lower p-tau217 levels in serum compared with plasma (<i>p</i> &lt; 0.0001) for both cohorts, while Lumipulse showed higher plasma levels in the Pitt-ADRC cohort but equivalent plasma and serum levels in the HCP cohort. Yet, strong correlations (rho &gt; 0.8) were observed between plasma and serum p-tau217 pairs for all methods. Both plasma and serum p-tau217 demonstrated strong classification accuracies to differentiate clinical AD from normal controls, with high AUC (up to 0.963) for all methods. The exception was the Pittsburgh assay, where plasma p-tau217 had significantly superior AUC to serum p-tau217 (plasma: 0.912, serum: 0.844). The rest of the assays had equivalent accuracies in both matrices. Serum p-tau217 performs equivalently as plasma p-tau217 for most assessed assays. Serum can be used as a substitute for plasma in the use of most p-tau217 assays to evaluate Aβ pathology in AD for both research and clinical purposes.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524693","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}

{"title":"Microglial α7-Nicotinic Acetylcholine Receptors Are Expressed in Mitochondria Rather Than on the Plasma Membrane: Roles in Mitochondrial Function","authors":"Yoki Nakamura,&nbsp;Riku Matsuda,&nbsp;Shogo Kuribayashi,&nbsp;Masatoshi Takemura,&nbsp;Kazue Hisaoka-Nakashima,&nbsp;Norimitsu Morioka","doi":"10.1111/jnc.70139","DOIUrl":"https://doi.org/10.1111/jnc.70139","url":null,"abstract":"<div>\u0000 \u0000 <p>The subcellular localization and cellular functions of the microglial α7-nicotinic acetylcholine receptor (α7-nAChR) were investigated in detail. Although α7-nAChR mRNA was present in microglia isolated from mouse brains by fluorescence-activated cell sorting, we observed low levels of mRNA for NACHO (novel acetylcholine receptor chaperone) and RIC3 (resistance to inhibitors of cholinesterase 3), which are crucial chaperones for the functional expression of α7-nAChR as an ionotropic receptor. Limited localization of α7-nAChR on the cell membrane of isolated microglia suggested an intracellular distribution of this receptor preferentially. To examine the function of α7-nAChR as a ligand-gated ion channel receptor, we treated primary cultured microglia with the α7-nAChR agonist choline; however, no increase in the intracellular calcium ion concentration was observed. Cell staining with α-bungarotoxin and an α7-nAChR antibody suggested that the α7-nAChR expressed in microglia is localized intracellularly, particularly in mitochondria, rather than at the cell membrane. Treatment of primary cultured microglia with choline significantly increased intracellular ATP levels, an indicator of mitochondrial function. This increase in ATP production was significantly suppressed by pretreatment with the α7-nAChR antagonist methyllycaconitine. In microglia with relatively low expression levels of NACHO and RIC3, the population of α7-nAChRs functioning as ion channel receptors at the plasma membrane is expected to be limited. This study reveals a newly described cellular function of microglial α7-nAChR in mitochondria. This finding improves our understanding of the multifaceted roles of α7-nAChRs in the central nervous system and opens new avenues for exploring their potential as a therapeutic target in microglia-related central nervous system disorders.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482260","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}

{"title":"GABA-Producing Levilactobacillus brevis LAB6 Mitigates Pentylenetetrazol-Induced Gut-Brain Dysregulation in SD Rats","authors":"Tushar Matta,&nbsp;Mahendra Bishnoi,&nbsp;Shiwangi Gupta,&nbsp;Aanchal Aggarwal,&nbsp;Kanwaljit Chopra,&nbsp;Kanthi Kiran Kondepudi","doi":"10.1111/jnc.70141","DOIUrl":"https://doi.org/10.1111/jnc.70141","url":null,"abstract":"<div>\u0000 \u0000 <p>Understanding the communication between the gut and brain has emerged as a new research avenue in neurological disorders like epilepsy, with increasing evidence pointing towards the influence of intestinal microbes on the central nervous system. Here, the protective effects of a psychobiotic strain <i>Levilactobacillus brevis</i> LAB6 MTCC 25662 supplementation against pentylenetetrazole (PTZ)-induced kindling in male Sprague Dawley rats was studied. Two GABA-producing strains <i>Levilactobacillus brevis</i> LAB6 and <i>Limosilactobacillus fermentum</i> LAB19 were screened for their protective effects against chronic PTZ-induced kindling. Chronic subconvulsive PTZ administration increased the convulsive activity, ultimately leading to generalized tonic–clonic seizures as indicated by a progressive rise in the seizure score, changes in endogenous antioxidants, and changes in inflammatory cytokines. Intervention with LAB6, but not LAB19, significantly attenuated these alterations and beneficially modulated gut health by increasing the production of short-chain fatty acids and promoting healthy gut microbes, suggesting strain-specific effects of LAB6. Further, colonization study with indocyanine green (ICG) labeled LAB6 was done, followed by dose-dependent protective efficacy of LAB6 in PTZ-induced kindling. A single dose administration (10¹⁰ CFU) showed that LAB6 translocated and adhered throughout the gastrointestinal (GI) tract within 8 h of administration and reached the distal colon and cecum. The supplementation of LAB6 at a medium dose of 2 × 10¹⁰ CFU was most efficient in restoring altered gut barrier functions, behavioral deficits, and modulation of peripheral GABA levels. Hence, it is a promising psychobiotic candidate for positively modulating gut-brain functions in epilepsy.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482262","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}

{"title":"The Impact of Splicing Dysregulation on Neuromuscular Disorders and Current Neuromuscular Genetic Therapies","authors":"Jing Wu,&nbsp;Shuxuan Yan,&nbsp;Yuqin Bian,&nbsp;Rui Liu,&nbsp;Xinxing Lyu,&nbsp;Zhaoxiang Zhang,&nbsp;Shuhong Huang,&nbsp;Tao Chen,&nbsp;Lin Cheng","doi":"10.1111/jnc.70133","DOIUrl":"https://doi.org/10.1111/jnc.70133","url":null,"abstract":"<p>Eukaryotic genes contain non-coding segments known as introns, which interrupt coding sequences. Consequently, eukaryotic transcription produces precursor messenger RNA (pre-mRNA) that relies on precise splicing to remove highly diverse introns from the genome and to generate the mature mRNA essential for maintaining normal cellular activities. The extensive heterogeneity of neurons necessitates complex splicing regulation, particularly alternative splicing, to ensure the accuracy of gene expression in neurogenesis, signal transduction, and synaptic function and to maintain stability and adaptability in the nervous system. With the improvement of genetic testing technology, aberrant splicing has been identified as a contributing factor to the pathogenesis of neuromuscular disorders (NMDs) such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM), Charcot–Marie–Tooth disease (CMT), myasthenia gravis (MG), and multiple sclerosis (MS). Studying the correlation between splicing defects and neuromuscular disorders is crucial for gaining a more comprehensive understanding of the pathogenesis of these diseases and for developing effective therapies. In this review, we introduce the intricate process and key factors of pre-mRNA splicing, with a focus on aberrant splicing and pathogenesis in several major neuromuscular disorders, providing an overview of the latest therapeutic strategies.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70133","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482261","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}

{"title":"SOD1 Protein Content in Human Central Nervous System and Peripheral Tissues","authors":"Laura Leykam,&nbsp;P. Andreas Jonsson,&nbsp;Karin M. E. Forsberg,&nbsp;Peter M. Andersen,&nbsp;Thomas Brännström,&nbsp;Stefan L. Marklund,&nbsp;Per Zetterström","doi":"10.1111/jnc.70136","DOIUrl":"https://doi.org/10.1111/jnc.70136","url":null,"abstract":"<p>Gene silencing therapy is an effective treatment for amyotrophic lateral sclerosis (ALS) patients carrying mutations in the superoxide dismutase-1 (<i>SOD1</i>) gene aiming to reduce noxious forms of SOD1 in the central nervous system (CNS). The normal steady-state level of SOD1 protein in human CNS is therefore of interest but is contested. In this work we have analyzed SOD1 protein content, total protein content, and SOD1 enzymatic activity in six areas of the CNS as well as in four peripheral tissues from sporadic and familial ALS patients and non-ALS controls. Our results show that SOD1 in the human CNS constitutes around 100 μg/g wet weight corresponding to about 0.16% of the total protein in the studied areas. Of the peripheral tissues analyzed, kidney and erythrocytes contain roughly equal amounts, liver higher, and skeletal muscle lower levels of SOD1 compared to the CNS. This data shows SOD1 protein levels around 10 times lower compared to previously published figures. However, SOD1 can still be considered an abundant protein considering that &gt; 12 000 proteins are expressed in human cells. There was no difference in SOD1 protein content between sporadic or familial ALS patients and control individuals. The level and activity of SOD1 are not deviating in the areas of the CNS that are most vulnerable to ALS. Instead, insufficient control of SOD1 structure and aggregation could be important factors behind the vulnerability of motor areas to SOD1 proteotoxicity.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339627","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}

{"title":"Towards Better and More Valid Zebrafish Models of Alzheimer's Disease: A Scientific Tribute to Prof. Mikhail I. Aghajanov","authors":"Maria M. Kotova,&nbsp;Adam Michael Stewart,&nbsp;Artem Grigoryan,&nbsp;Sanobar Shariff,&nbsp;Foad Mirzaei,&nbsp;Burhan Kantawala,&nbsp;Karen Dilbaryan,&nbsp;Murilo S. de Abreu,&nbsp;David S. Galstryan,&nbsp;Jiahao Cui,&nbsp;Longen Yang,&nbsp;Konstantin B. Yenkoyan,&nbsp;Allan V. Kalueff","doi":"10.1111/jnc.70090","DOIUrl":"https://doi.org/10.1111/jnc.70090","url":null,"abstract":"<p>The most common form of dementia, Alzheimer's disease (AD) is a severely debilitating neurodegenerative disorder that afflicts over 50 million people globally. Despite extensive its research using various animal models, nearly all promising AD treatments have failed in clinical trials. Zebrafish (<i>Danio rerio</i>) have recently emerged as a valuable alternative to traditional (rodent) models of AD, possessing conserved neurotransmitter systems and disease pathways with humans, as well as orthologs for key genes associated with neurodegenerative disease. Here, we review recent advances and applications of zebrafish to study the pathogenesis of AD, and discuss the advantages, limitations, and potential future directions of research utilizing zebrafish AD models. This paper is dedicated to the late Professor Mikhail I. Aghajanov (1939–2024), a prominent Armenian neurochemist and a true crusader for fundamental AD research.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339625","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}

{"title":"cAMP-Response Element (CRE)-Mediated Transcription by CRE-Binding Protein (CREB) Is Essential for Human Tryptophan Hydroxylase 2 Gene Expression","authors":"Yukino Nawa,&nbsp;Hanae Kaneko,&nbsp;Masaaki Tsubonoya,&nbsp;Tomoko Hiroi,&nbsp;Ryoya Takahashi,&nbsp;Tomoo Sato,&nbsp;Hiroaki Matsui","doi":"10.1111/jnc.70138","DOIUrl":"https://doi.org/10.1111/jnc.70138","url":null,"abstract":"<div>\u0000 \u0000 <p>Human tryptophan hydroxylase 2 (hTPH2), a rate-limiting enzyme in the synthesis of central serotonin, is dysregulated in various neuropsychiatric disorders. However, the regulatory mechanisms underlying <i>TPH2</i> gene expression remain unknown. Here, we aimed to analyze the cAMP signaling-mediated activation of hTPH2 promoter activity involving an inverted cAMP-response element (CRE; 5′-TAACGTCA-3′; −243/−236 relative to the transcription start site, +1). A 2-kb region of the <i>TPH2</i> gene (−1850/+141; except +10/+121, a region containing repression elements) was cloned into pGL4-Basic to construct a luciferase reporter plasmid. Promoter activity was assessed via transient transfection of RN46A cells derived from rat raphe neurons. Forskolin-induced increase in cAMP levels enhanced hTPH2 promoter activity, which was significantly suppressed by the protein kinase A (PKA) inhibitor, H-89, or CRE mutants. Gel mobility shift assays and chromatin immunoprecipitation assays confirmed the specific binding of CRE-binding protein (CREB) to CRE. hTPH2 promoter activity was decreased by endogenous CREB knockdown. Overexpression of PKAα catalytic subunit and CREB tended to increase the hTPH2 promoter activity. Furthermore, overexpression of CREB-regulated transcription co-activator 1 (CRTC1) the principal CRTC isoform in the brain, with PKAα/CREB significantly increased the hTPH2 promoter activity. In contrast, under PKAα/CRTC1 overexpression conditions, hTPH2 promoter activity was slightly decreased by the overexpression of R133A-CREB (defective for phosphorylation by PKA) and further decreased by the overexpression of R314A-CREB (defective for interaction with CRTC). Overall, our results suggest that high cAMP levels regulate the hTPH2 promoter activity mainly via PKA and its downstream effectors, such as CREB. Moreover, PKA–CRTC signaling stimulates <i>TPH2</i> gene transcription upon CREB activation.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331869","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}