Obsessive–compulsive disorder (OCD) affects 1–3% of the global population and ranks among the top ten most disabling medical conditions. While abnormalities in cortico-striato-thalamo-cortical circuits have been implicated in OCD pathophysiology, the molecular mechanisms underlying these neural aberrations remain incompletely understood. Protein palmitoylation, a reversible post-translational modification, is essential for neuronal development and synaptic function, potentially affecting neurotransmitter systems linked to OCD. We employed Mendelian randomization (MR) to explore causal relationships between the expression of palmitoylation-related genes, imaging-derived phenotypes (IDPs), and OCD susceptibility. Analysis of 22 palmitoylation-related genes revealed that decreased expression of the palmitoyl acyltransferase ZDHHC4 significantly increases OCD risk (OR = 0.882, 95% CI: 0.831–0.935, p = 2.73 × 10−5), a finding that remained robust across multiple sensitivity analyses. In a survey of 183 IDPs associated with OCD, ZDHHC4 expression significantly influenced 46 imaging measures. Mediation analysis revealed that the IDP ICA100 edge 531, representing functional connectivity between the left dorsolateral prefrontal cortex and bilateral orbitofrontal cortex, significantly mediated the relationship between ZDHHC4 expression and OCD risk (19.9%, p = 0.005). These findings establish a novel causal pathway linking ZDHHC4-mediated palmitoylation to altered brain activity in frontal-orbital circuits and subsequent OCD susceptibility. This integrated molecular-neural circuit framework provides new insights into OCD pathophysiology and identifies palmitoylation pathways as potential therapeutic targets for this debilitating neuropsychiatric disorder.
{"title":"ZDHHC4 Influences Obsessive–Compulsive Disorder Risk Through Imaging-Derived Phenotypes: A Mendelian Randomization Study","authors":"Ying Huang, Huanxian Luo, Jieping Huang, Xuejiao Hou","doi":"10.1007/s12031-025-02391-y","DOIUrl":"10.1007/s12031-025-02391-y","url":null,"abstract":"<div><p>Obsessive–compulsive disorder (OCD) affects 1–3% of the global population and ranks among the top ten most disabling medical conditions. While abnormalities in cortico-striato-thalamo-cortical circuits have been implicated in OCD pathophysiology, the molecular mechanisms underlying these neural aberrations remain incompletely understood. Protein palmitoylation, a reversible post-translational modification, is essential for neuronal development and synaptic function, potentially affecting neurotransmitter systems linked to OCD. We employed Mendelian randomization (MR) to explore causal relationships between the expression of palmitoylation-related genes, imaging-derived phenotypes (IDPs), and OCD susceptibility. Analysis of 22 palmitoylation-related genes revealed that decreased expression of the palmitoyl acyltransferase ZDHHC4 significantly increases OCD risk (OR = 0.882, 95% CI: 0.831–0.935, <i>p</i> = 2.73 × 10<sup>−5</sup>), a finding that remained robust across multiple sensitivity analyses. In a survey of 183 IDPs associated with OCD, ZDHHC4 expression significantly influenced 46 imaging measures. Mediation analysis revealed that the IDP ICA100 edge 531, representing functional connectivity between the left dorsolateral prefrontal cortex and bilateral orbitofrontal cortex, significantly mediated the relationship between ZDHHC4 expression and OCD risk (19.9%, <i>p</i> = 0.005). These findings establish a novel causal pathway linking ZDHHC4-mediated palmitoylation to altered brain activity in frontal-orbital circuits and subsequent OCD susceptibility. This integrated molecular-neural circuit framework provides new insights into OCD pathophysiology and identifies palmitoylation pathways as potential therapeutic targets for this debilitating neuropsychiatric disorder.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-02DOI: 10.1007/s12031-025-02387-8
Shahid Ishaq, Iqbal Ali Shah, Shin-Da Lee, Bor-Tsang Wu
This study conducted a transcriptomic analysis to identify differentially expressed genes involved in immune-related pathways in the striatum of various Parkinson’s disease (PD) mouse strains. Data were obtained from the NCBI GEO database, focusing on PD in vivo studies of the striatum. Microarray and RNA-seq datasets were analyzed using the limma package via GEO2R and DESeq2, respectively, with p-values combined and adjusted to FDR < 0.05. Out of 63 studies, nine were included, resulting in 18 datasets. Of the 13,065 significant genes, 179 were differentially expressed and enriched, leading to the identification of 308 pathways. Among the nine immune-related pathways, the three most significant were phagosome-related immune modulation with eleven key upregulated genes, cytokine-cytokine receptor interaction with twelve key genes (eleven upregulated and one highly downregulated), and FcγR-mediated phagocytosis with seven key upregulated genes. These pathways, particularly the interaction between phagosome modulation and FcγR-mediated phagocytosis, highlighted critical roles in immune response modulation, neuronal inflammation, and phagocytosis, contributing to the progression of pathogenesis in the striatum of PD mouse models.
{"title":"Transcriptomic Analysis of Immune-Related Genes in the Striatum of Parkinson’s Disease Brain Across Mouse Strains","authors":"Shahid Ishaq, Iqbal Ali Shah, Shin-Da Lee, Bor-Tsang Wu","doi":"10.1007/s12031-025-02387-8","DOIUrl":"10.1007/s12031-025-02387-8","url":null,"abstract":"<div><p>This study conducted a transcriptomic analysis to identify differentially expressed genes involved in immune-related pathways in the striatum of various Parkinson’s disease (PD) mouse strains. Data were obtained from the NCBI GEO database, focusing on PD in vivo studies of the striatum. Microarray and RNA-seq datasets were analyzed using the limma package via GEO2R and DESeq2, respectively, with <i>p</i>-values combined and adjusted to FDR < 0.05. Out of 63 studies, nine were included, resulting in 18 datasets. Of the 13,065 significant genes, 179 were differentially expressed and enriched, leading to the identification of 308 pathways. Among the nine immune-related pathways, the three most significant were phagosome-related immune modulation with eleven key upregulated genes, cytokine-cytokine receptor interaction with twelve key genes (eleven upregulated and one highly downregulated), and FcγR-mediated phagocytosis with seven key upregulated genes. These pathways, particularly the interaction between phagosome modulation and FcγR-mediated phagocytosis, highlighted critical roles in immune response modulation, neuronal inflammation, and phagocytosis, contributing to the progression of pathogenesis in the striatum of PD mouse models.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation. The activation of microglia is closely linked to PND, although the precise mechanism remains unclear. Gamma oscillations (30–100 Hz) are associated with higher cognitive functions, including attention. The aim of this study was to investigate the mechanism by which microglial activation in PND disrupts gamma oscillations. The study utilized 18-month-old male C57BL/6 J mice and established a PND model through exploratory laparotomy. The results of both Contextual Fear Conditioning (CFC) and Morris Water Maze (MWM) experiments demonstrated that exploratory laparotomy could lead to hippocampus-dependent neurocognitive dysfunction in aged mice. We observed that exploratory laparotomy induced the transformation of microglia in the hippocampus of aged mice into an activated phenotype characterized by enlarged cell bodies and shortened processes. This transformation was accompanied by a significant increase in the expression levels of pro-inflammatory factors in hippocampal tissue, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement. Additionally, we found that the expression levels of hippocampal parvalbumin (PV) and glutamate decarboxylase 67 (GAD67) were significantly reduced following exploratory laparotomy, which was accompanied by disturbed gamma oscillations. Depletion of microglia restored the expression levels of PV and GAD67 and significantly improved the disturbances in gamma oscillations. These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.
{"title":"Gamma Oscillation Disruption Induced By Microglial Activation Contributes to Perioperative Neurocognitive Disorders in Aged Mice","authors":"Shiyu Hao, Qidi Zhang, Xianzheng Zhang, Zunsai Feng, Jiangnan Wu, Ziqing Xu, Jingjing Li, Gongming Wang","doi":"10.1007/s12031-025-02380-1","DOIUrl":"10.1007/s12031-025-02380-1","url":null,"abstract":"<p>Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation. The activation of microglia is closely linked to PND, although the precise mechanism remains unclear. Gamma oscillations (30–100 Hz) are associated with higher cognitive functions, including attention. The aim of this study was to investigate the mechanism by which microglial activation in PND disrupts gamma oscillations. The study utilized 18-month-old male C57BL/6 J mice and established a PND model through exploratory laparotomy. The results of both Contextual Fear Conditioning (CFC) and Morris Water Maze (MWM) experiments demonstrated that exploratory laparotomy could lead to hippocampus-dependent neurocognitive dysfunction in aged mice. We observed that exploratory laparotomy induced the transformation of microglia in the hippocampus of aged mice into an activated phenotype characterized by enlarged cell bodies and shortened processes. This transformation was accompanied by a significant increase in the expression levels of pro-inflammatory factors in hippocampal tissue, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement. Additionally, we found that the expression levels of hippocampal parvalbumin (PV) and glutamate decarboxylase 67 (GAD67) were significantly reduced following exploratory laparotomy, which was accompanied by disturbed gamma oscillations. Depletion of microglia restored the expression levels of PV and GAD67 and significantly improved the disturbances in gamma oscillations. These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This is the first study in Iraq to integrate socioeconomic, genetic, and oxidative stress markers in MS patients, revealing unique associations between HLA-DRB1 polymorphisms and relapsing–remitting MS (RRMS). This work investigated the demographic, clinical, oxidative stress, and molecular aspects influencing quality of life in multiple sclerosis patients in Sulaymaniyah, Iraq. A cross-sectional study was undertaken with 63 MS patients and 20 healthy controls to evaluate quality of life using the Multiple Sclerosis Quality of Life-54 (MSQoL-54) questionnaire. We compiled demographic and clinical information, including age, sex, educational level, socioeconomic level, multiple sclerosis phenotype, disease duration, and Expanded Disability Status Scale (EDSS) scores. In this work, single nucleotide polymorphism (SNP) of HLA-DRB1 was investigated in conjunction with oxidative stress markers, including MDA, 8-OHdG, and GPx activity, to the expression of the NRF2 gene. Significant relationships (p < 0.05) between quality of life and crucial variables, including the degree of the disease, level of education, socioeconomic level, and oxidative stress markers, were revealed by statistical analysis. MDA and 8-OHdG levels tightly predicted NRF2 expression (R2 = 0.713, p < 0.001 according to regression analysis). This result draws attention to an antioxidant response seeking to offset its lack of potency. All MS subtypes showed noticeably higher NRF2 expression than controls, according to post hoc analysis. PPMS showed the highest overexpression (p < 0.001). The results indicated the importance of oxidative stress markers in multiple sclerosis and how it affects quality of life. For this reason, personalized treatments must target both oxidative stress and socioeconomic status to help patients get better, especially in underdeveloped areas. Besides this, the study offers important information for legislators and medical practitioners creating thorough, patient-centered care plans to improve MS management. Furthermore, serum vitamin D3 levels varied greatly among MS subtypes (p = 0.008); PPMS patients had the lowest levels. Though p = 0.162, vitamin B12 levels did not approach statistical relevance; lower levels were observed in progressive MS forms, implying a possible function in disease pathogenesis. In this work, single nucleotide polymorphism (SNP) of HLA-DRB1 has been investigated together with oxidative stress markers including MDA, 8-OHdG, and GPx activity to NRF2 gene expression. Two RRMS patients showed the T risk allele (G > A transition at rs3135), indicating a possible genetic predisposition to MS in this cohort based on SNP analysis. Moreover, MS patients and healthy controls underwent genotyping analysis utilizing Sanger sequencing to evaluate the distribution of HLA-DRB1 rs3135388. More often detected in MS subtypes, especially in RRMS forms, the T allele supports a gen
这是伊拉克首个整合MS患者社会经济、遗传和氧化应激标志物的研究，揭示了HLA-DRB1多态性与复发缓解型MS （RRMS）之间的独特关联。本研究调查了伊拉克苏莱曼尼亚地区多发性硬化症患者的人口统计学、临床、氧化应激和分子方面对生活质量的影响。本研究对63名MS患者和20名健康对照者进行了横断面研究，使用多发性硬化症生活质量-54 （MSQoL-54）问卷来评估生活质量。我们收集了人口统计学和临床信息，包括年龄、性别、教育水平、社会经济水平、多发性硬化症表型、疾病持续时间和扩展残疾状态量表（EDSS）评分。在这项工作中，我们研究了HLA-DRB1的单核苷酸多态性（SNP）与氧化应激标志物（包括MDA、8-OHdG和GPx活性）对NRF2基因表达的影响。显著相关性（p 2 = 0.713， p A在rs3135处发生转变），表明基于SNP分析，该队列中可能存在MS遗传易感性。此外，利用Sanger测序对MS患者和健康对照进行基因分型分析，评估HLA-DRB1 rs3135388的分布。T等位基因更常在MS亚型中检测到，特别是在RRMS亚型中，它支持与氧化应激失调相关的遗传易感性。
{"title":"Demographic, Clinical, and Molecular Determinants of Quality of Life and Oxidative Stress in Multiple Sclerosis: A Cross-Sectional Study from Sulaymaniyah, Iraq","authors":"Dlzar Dlshad Ghafoor, Dlshad Omar Ahmed, Sarwer Jamal Al-Bajalan","doi":"10.1007/s12031-025-02386-9","DOIUrl":"10.1007/s12031-025-02386-9","url":null,"abstract":"<div><p>This is the first study in Iraq to integrate socioeconomic, genetic, and oxidative stress markers in MS patients, revealing unique associations between HLA-DRB1 polymorphisms and relapsing–remitting MS (RRMS). This work investigated the demographic, clinical, oxidative stress, and molecular aspects influencing quality of life in multiple sclerosis patients in Sulaymaniyah, Iraq. A cross-sectional study was undertaken with 63 MS patients and 20 healthy controls to evaluate quality of life using the Multiple Sclerosis Quality of Life-54 (MSQoL-54) questionnaire. We compiled demographic and clinical information, including age, sex, educational level, socioeconomic level, multiple sclerosis phenotype, disease duration, and Expanded Disability Status Scale (EDSS) scores. In this work, single nucleotide polymorphism (SNP) of HLA-DRB1 was investigated in conjunction with oxidative stress markers, including MDA, 8-OHdG, and GPx activity, to the expression of the NRF2 gene. Significant relationships (<i>p</i> < 0.05) between quality of life and crucial variables, including the degree of the disease, level of education, socioeconomic level, and oxidative stress markers, were revealed by statistical analysis. MDA and 8-OHdG levels tightly predicted NRF2 expression (<i>R</i><sup>2</sup> = 0.713, <i>p</i> < 0.001 according to regression analysis). This result draws attention to an antioxidant response seeking to offset its lack of potency. All MS subtypes showed noticeably higher NRF2 expression than controls, according to post hoc analysis. PPMS showed the highest overexpression (<i>p</i> < 0.001). The results indicated the importance of oxidative stress markers in multiple sclerosis and how it affects quality of life. For this reason, personalized treatments must target both oxidative stress and socioeconomic status to help patients get better, especially in underdeveloped areas. Besides this, the study offers important information for legislators and medical practitioners creating thorough, patient-centered care plans to improve MS management. Furthermore, serum vitamin D3 levels varied greatly among MS subtypes (<i>p</i> = 0.008); PPMS patients had the lowest levels. Though <i>p</i> = 0.162, vitamin B12 levels did not approach statistical relevance; lower levels were observed in progressive MS forms, implying a possible function in disease pathogenesis. In this work, single nucleotide polymorphism (SNP) of HLA-DRB1 has been investigated together with oxidative stress markers including MDA, 8-OHdG, and GPx activity to NRF2 gene expression. Two RRMS patients showed the T risk allele (G > A transition at rs3135), indicating a possible genetic predisposition to MS in this cohort based on SNP analysis. Moreover, MS patients and healthy controls underwent genotyping analysis utilizing Sanger sequencing to evaluate the distribution of HLA-DRB1 rs3135388. More often detected in MS subtypes, especially in RRMS forms, the T allele supports a gen","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-28DOI: 10.1007/s12031-025-02389-6
Xinglong Lu, Zhenghua Wu, Xuanxuan Huang, Zipeng Gong, Yin Cao
Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a critical mechanism underlying the pathophysiological effects of sleep deprivation (SD) and neurological consequences. Recent studies have highlighted the significant neuroprotective role of the GABAB receptor. This study aimed to investigate the effects of SD-induced ferroptosis on the expression of the GABAB receptor in the hippocampus. Thirty-six male C57BL/6 mice were used in this study, with twenty-four subjected to SD through a modified multiple-platform water method and twelve serving as controls. Learning and memory capacities were evaluated using the Morris water maze, while hippocampal neuron morphology was examined via Nissl staining. Biochemical assays were conducted to measure levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and lactate dehydrogenase (LDH) in serum, hippocampal tissue, and cultured cells. Transmission electron microscopy and flow cytometry were employed to observe mitochondrial alterations and reactive oxygen species levels. Western blotting was performed to analyze the expression of the GABAB receptor and ferroptosis-related proteins. SD resulted in impaired learning and memory, hippocampal neuronal damage, morphological alterations in hippocampal neuronal mitochondria, and abnormal expression of the GABAB receptor and ferroptosis-related proteins in the hippocampus of mice. Similarly, in vitro experiment, we observed a increase in oxidative stress, mitochondrial structural damage, aberrant expression of the GABAB receptor, and changes in ferroptosis-related protein levels. SD induced ferroptosis in hippocampal neurons of mice, reduced the expression of the GABAB receptor, and led to impairments in learning and memory.
{"title":"Sleep Deprivation Induces Ferroptosis and Reduces the Expression of GABAB Receptor in Mice","authors":"Xinglong Lu, Zhenghua Wu, Xuanxuan Huang, Zipeng Gong, Yin Cao","doi":"10.1007/s12031-025-02389-6","DOIUrl":"10.1007/s12031-025-02389-6","url":null,"abstract":"<div><p>Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a critical mechanism underlying the pathophysiological effects of sleep deprivation (SD) and neurological consequences. Recent studies have highlighted the significant neuroprotective role of the GABA<sub>B</sub> receptor. This study aimed to investigate the effects of SD-induced ferroptosis on the expression of the GABA<sub>B</sub> receptor in the hippocampus. Thirty-six male C57BL/6 mice were used in this study, with twenty-four subjected to SD through a modified multiple-platform water method and twelve serving as controls. Learning and memory capacities were evaluated using the Morris water maze, while hippocampal neuron morphology was examined via Nissl staining. Biochemical assays were conducted to measure levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and lactate dehydrogenase (LDH) in serum, hippocampal tissue, and cultured cells. Transmission electron microscopy and flow cytometry were employed to observe mitochondrial alterations and reactive oxygen species levels. Western blotting was performed to analyze the expression of the GABA<sub>B</sub> receptor and ferroptosis-related proteins. SD resulted in impaired learning and memory, hippocampal neuronal damage, morphological alterations in hippocampal neuronal mitochondria, and abnormal expression of the GABA<sub>B</sub> receptor and ferroptosis-related proteins in the hippocampus of mice. Similarly, in vitro experiment, we observed a increase in oxidative stress, mitochondrial structural damage, aberrant expression of the GABA<sub>B</sub> receptor, and changes in ferroptosis-related protein levels. SD induced ferroptosis in hippocampal neurons of mice, reduced the expression of the GABA<sub>B</sub> receptor, and led to impairments in learning and memory.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-28DOI: 10.1007/s12031-025-02392-x
Hawnaz Mohammad Ismael, Parween Abdulsamad Ismail
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early-onset social communication deficits, restricted/repetitive behaviors, and sensory sensitivities. Although ASD is predominantly influenced by genetic factors, accumulating evidence implicates oxidative stress as a contributing mechanism in its pathophysiology. This study included a total of 89 children, of whom 60 were diagnosed with ASD and 29 were healthy controls. The severity of autism was assessed according to the criteria established in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The study measured the levels of 8-hydroxydeoxyguanosine (8-OHdG), 8-oxoguanine DNA glycosylase 1 (OGG1), 3-nitrotyrosine (3-NT), and advanced oxidation protein products (AOPP) using the sandwich ELISA method. The results demonstrate a significant elevation of 8-OHdG in the ASD group compared to the control group (p = 0.043), which positively correlated with ASD symptom severity (p = 0.029). Conversely, OGG1 levels were significantly reduced in ASD (p = 0.0004) and were strongly linked to more severe ASD symptoms (p = 0.0001). Moreover, both 3-NT (p = 0.0005) and AOPP (p = 0.043) levels were significantly elevated in ASD and showed positive correlations with ASD severity (p = 0.0043 and p = 0.046, respectively). The present findings demonstrate marked elevation in oxidative DNA damage, evidenced by increased levels of 8-OHdG and decreased concentrations of OGG1, as well as enhanced protein oxidation, reflected by heightened 3-NT and AOPP levels, in children diagnosed with ASD. The strong correlations observed between elevated oxidative stress biomarkers, diminished OGG1 levels, and increased ASD severity underscore their utility as potential indicators of disease severity and provide key mechanistic insights into ASD pathophysiology.
{"title":"Investigating Oxidative Stress and Impaired DNA Repair Capacity as Diagnostic Biomarkers in Autism Spectrum Disorder","authors":"Hawnaz Mohammad Ismael, Parween Abdulsamad Ismail","doi":"10.1007/s12031-025-02392-x","DOIUrl":"10.1007/s12031-025-02392-x","url":null,"abstract":"<div><p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early-onset social communication deficits, restricted/repetitive behaviors, and sensory sensitivities. Although ASD is predominantly influenced by genetic factors, accumulating evidence implicates oxidative stress as a contributing mechanism in its pathophysiology. This study included a total of 89 children, of whom 60 were diagnosed with ASD and 29 were healthy controls. The severity of autism was assessed according to the criteria established in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The study measured the levels of 8-hydroxydeoxyguanosine (8-OHdG), 8-oxoguanine DNA glycosylase 1 (OGG1), 3-nitrotyrosine (3-NT), and advanced oxidation protein products (AOPP) using the sandwich ELISA method. The results demonstrate a significant elevation of 8-OHdG in the ASD group compared to the control group (<i>p</i> = 0.043), which positively correlated with ASD symptom severity (<i>p</i> = 0.029). Conversely, OGG1 levels were significantly reduced in ASD (<i>p</i> = 0.0004) and were strongly linked to more severe ASD symptoms (<i>p</i> = 0.0001). Moreover, both 3-NT (<i>p</i> = 0.0005) and AOPP (<i>p</i> = 0.043) levels were significantly elevated in ASD and showed positive correlations with ASD severity (<i>p</i> = 0.0043 and <i>p</i> = 0.046, respectively). The present findings demonstrate marked elevation in oxidative DNA damage, evidenced by increased levels of 8-OHdG and decreased concentrations of OGG1, as well as enhanced protein oxidation, reflected by heightened 3-NT and AOPP levels, in children diagnosed with ASD. The strong correlations observed between elevated oxidative stress biomarkers, diminished OGG1 levels, and increased ASD severity underscore their utility as potential indicators of disease severity and provide key mechanistic insights into ASD pathophysiology.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent studies have shown that palmitoylation is involved in ischemic stroke(IS). However, the role of palmitoylation in IS has not been systematically investigated. The aim of this study is to explore the causal relationship and mechanism between palmitoylation genes, metabolites, and IS using Mendelian randomization (MR) method. The GWAS data of IS from GISCOME network database, the palmitoylation gene data from eQTLGen database, and the metabolite data from GWAS database were used in this study. Two-sample MR analysis, summary-based Mendelian randomization (SMR) analysis, and mediation analysis were used. Firstly, two-sample MR analysis was used to evaluate the causal relationship between palmitoylation genes and IS. The SMR method was then used to verify the correlation between gene expression and IS. The GSE140275 dataset of GEO database was used to test the expression of palmitoylation genes. Mediation analysis was used to explore the mediating effect between palmitoylation gene expression and metabolites and IS (metabolites are mediators, genes are exposures). The high expression of ZDHHC13 gene is significantly negatively correlated with the risk of IS. ZDHHC13 indirectly affects the occurrence of IS by regulating Mannonate metabolites. Sensitivity and SMR analyses supported our findings, indicating high statistical robustness. Based on the observational results serum data set of IS patients, the expression of ZDHHC13 is decreased after IS. However, ZDHHC13 has a protective effect before the occurrence of ischemic stroke, which MR analysis result is contrary to observational results. This study reveals the role of ZDHHC13 in the progression of IS by regulating Mannonate metabolites and provides potential clinical application prospects for ZDHHC13 as a biomarker or preventive target for early diagnosis and treatment of IS.
{"title":"ZDHHC13 Reduces the Risk of Ischemic Stroke by Regulating Metabolites","authors":"Zhen Wei, Chunshu Rong, Wei He, Xu Wang, Dexi Zhao","doi":"10.1007/s12031-025-02378-9","DOIUrl":"10.1007/s12031-025-02378-9","url":null,"abstract":"<div><p>Recent studies have shown that palmitoylation is involved in ischemic stroke(IS). However, the role of palmitoylation in IS has not been systematically investigated. The aim of this study is to explore the causal relationship and mechanism between palmitoylation genes, metabolites, and IS using Mendelian randomization (MR) method. The GWAS data of IS from GISCOME network database, the palmitoylation gene data from eQTLGen database, and the metabolite data from GWAS database were used in this study. Two-sample MR analysis, summary-based Mendelian randomization (SMR) analysis, and mediation analysis were used. Firstly, two-sample MR analysis was used to evaluate the causal relationship between palmitoylation genes and IS. The SMR method was then used to verify the correlation between gene expression and IS. The GSE140275 dataset of GEO database was used to test the expression of palmitoylation genes. Mediation analysis was used to explore the mediating effect between palmitoylation gene expression and metabolites and IS (metabolites are mediators, genes are exposures). The high expression of ZDHHC13 gene is significantly negatively correlated with the risk of IS. ZDHHC13 indirectly affects the occurrence of IS by regulating Mannonate metabolites. Sensitivity and SMR analyses supported our findings, indicating high statistical robustness. Based on the observational results serum data set of IS patients, the expression of ZDHHC13 is decreased after IS. However, ZDHHC13 has a protective effect before the occurrence of ischemic stroke, which MR analysis result is contrary to observational results. This study reveals the role of ZDHHC13 in the progression of IS by regulating Mannonate metabolites and provides potential clinical application prospects for ZDHHC13 as a biomarker or preventive target for early diagnosis and treatment of IS.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-21DOI: 10.1007/s12031-025-02364-1
Ahmed M. Zain, Khalil A. El-Halfaway, Ahmed A. Abdel Megeed, Ahmed Abd Elbadee, Hany Khalil
Stroke is the second leading cause of death globally and a major contributor to disability. Developing countries report the highest rates of stroke, with ischemic stroke being the most prevalent type. This study aimed to explore the potential association between specific single nucleotide polymorphisms (SNPs) and thrombotic strokes in Egyptian patients, as well as the role of DNA methylation in the promoter regions of genes associated with these SNPs. The study involved 100 adult patients who were consecutively admitted to the International Medical Center. These patients, diagnosed with acute ischemic stroke, were compared to age-matched control subjects (± 3 years). Molecular analysis was conducted on six thrombosis-related SNPs: FV (R506Q, H1299R, Y1702C), FII (G20210A), and MTHFR (C677T, A1298C) using blood samples from both stroke patients and healthy controls. DNA methylation in the promoter regions of the FV, FII, and MTHFR genes was assessed through a sodium bisulfite conversion protocol and genomic DNA digestion with the methylation-dependent restriction enzyme MspJI, using specific primers for the promoter regions of FV, FII, and MTHFR in all derived samples. The biochemical analysis of the derived samples revealed elevated levels of homocysteine, ESR, and LDL in stroke patients, alongside reduced levels of both vitamin B12 and serum folate. The SNP analysis of samples from healthy controls and stroke patients, conducted using the TaqMan™ SNP genotyping assay, identified the homozygous SNPs in the FV, FII, and MTHFR genes. The results clearly show that the MTHFR C677T heterozygous mutation is present in nearly all stroke patient samples, with a very low likelihood of this mutation co-occurring with SNP mutations in the other indicated genes. Analysis of methylation activities in the promoter regions of the indicated genes showed hypermethylation in the MTHFR promoter region, while methylation levels in the FV and FII promoter regions were normal. The analysis showed increased methylation of cytosine nucleotide in the MTHFR promoter region, potentially inhibiting MTHFR expression and contributing to the development of thrombotic strokes in patients. Overall, the data support an association between the MTHFR C677T mutation, hypermethylation in its promoter region, and stroke development in the study participants.
{"title":"Methylomic Changes in MTHFR Promoter Region, along with the Heterozygous C677T Polymorphism, Contribute to the Risk of Thrombotic Stroke","authors":"Ahmed M. Zain, Khalil A. El-Halfaway, Ahmed A. Abdel Megeed, Ahmed Abd Elbadee, Hany Khalil","doi":"10.1007/s12031-025-02364-1","DOIUrl":"10.1007/s12031-025-02364-1","url":null,"abstract":"<div><p>Stroke is the second leading cause of death globally and a major contributor to disability. Developing countries report the highest rates of stroke, with ischemic stroke being the most prevalent type. This study aimed to explore the potential association between specific single nucleotide polymorphisms (SNPs) and thrombotic strokes in Egyptian patients, as well as the role of DNA methylation in the promoter regions of genes associated with these SNPs. The study involved 100 adult patients who were consecutively admitted to the International Medical Center. These patients, diagnosed with acute ischemic stroke, were compared to age-matched control subjects (± 3 years). Molecular analysis was conducted on six thrombosis-related SNPs: FV (R506Q, H1299R, Y1702C), FII (G20210A), and MTHFR (C677T, A1298C) using blood samples from both stroke patients and healthy controls. DNA methylation in the promoter regions of the FV, FII, and MTHFR genes was assessed through a sodium bisulfite conversion protocol and genomic DNA digestion with the methylation-dependent restriction enzyme MspJI, using specific primers for the promoter regions of FV, FII, and MTHFR in all derived samples. The biochemical analysis of the derived samples revealed elevated levels of homocysteine, ESR, and LDL in stroke patients, alongside reduced levels of both vitamin B12 and serum folate. The SNP analysis of samples from healthy controls and stroke patients, conducted using the TaqMan™ SNP genotyping assay, identified the homozygous SNPs in the FV, FII, and MTHFR genes. The results clearly show that the MTHFR C677T heterozygous mutation is present in nearly all stroke patient samples, with a very low likelihood of this mutation co-occurring with SNP mutations in the other indicated genes. Analysis of methylation activities in the promoter regions of the indicated genes showed hypermethylation in the MTHFR promoter region, while methylation levels in the FV and FII promoter regions were normal. The analysis showed increased methylation of cytosine nucleotide in the MTHFR promoter region, potentially inhibiting MTHFR expression and contributing to the development of thrombotic strokes in patients. Overall, the data support an association between the MTHFR C677T mutation, hypermethylation in its promoter region, and stroke development in the study participants.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16DOI: 10.1007/s12031-025-02373-0
Tianshu Zhu, Yue Wang, Han Wang, Zheyu Xu, Peng-Fei Zhang, Zhiming Lu
DNA methylation plays a crucial role in the onset and progression of Alzheimer’s disease (AD). Genome-wide methylation analysis of multi-tissue data can provide insights into the pathology and diagnostic biomarkers of AD. Computational tools were employed to identify pathways associated with AD and to develop a poly-methylation score (PMS). Key genes within the identified pathways were determined through module analysis and protein–protein interaction networks followed by validation in β-amyloid 42-induced cellular models. Linear mixed-effects model was used to investigate the longitudinal relationship between PMS and changes in AD phenotypes. AD-related pathways exhibited tissue specificity. The key genes in blood, frontal cortex, neurons, and glial cells were THBS1, TGFB1, HIF1A, and KLF4, respectively. Furthermore, the expression alterations of these genes were validated in three cellular models (SH-SY5Y, HMC3, and THP-1). Notably, higher PMS was significantly correlated with accelerated declines in cerebral metabolic rate and cognitive function. Using machine learning to analyze methylation data and identify key genes in AD patients enhanced our understanding of AD pathogenesis. Further research is needed to validate the potential of these key genes as intervention targets for AD.
{"title":"Multi-tissue Methylation Analysis of Alzheimer’s Disease: Insights into Pathways, Modules, and Key Genes","authors":"Tianshu Zhu, Yue Wang, Han Wang, Zheyu Xu, Peng-Fei Zhang, Zhiming Lu","doi":"10.1007/s12031-025-02373-0","DOIUrl":"10.1007/s12031-025-02373-0","url":null,"abstract":"<div><p>DNA methylation plays a crucial role in the onset and progression of Alzheimer’s disease (AD). Genome-wide methylation analysis of multi-tissue data can provide insights into the pathology and diagnostic biomarkers of AD. Computational tools were employed to identify pathways associated with AD and to develop a poly-methylation score (PMS). Key genes within the identified pathways were determined through module analysis and protein–protein interaction networks followed by validation in β-amyloid 42-induced cellular models. Linear mixed-effects model was used to investigate the longitudinal relationship between PMS and changes in AD phenotypes. AD-related pathways exhibited tissue specificity. The key genes in blood, frontal cortex, neurons, and glial cells were <i>THBS1</i>, <i>TGFB1</i>, <i>HIF1A</i>, and <i>KLF4</i>, respectively. Furthermore, the expression alterations of these genes were validated in three cellular models (SH-SY5Y, HMC3, and THP-1). Notably, higher PMS was significantly correlated with accelerated declines in cerebral metabolic rate and cognitive function. Using machine learning to analyze methylation data and identify key genes in AD patients enhanced our understanding of AD pathogenesis. Further research is needed to validate the potential of these key genes as intervention targets for AD.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The rising incidence of brain diseases parallels the global trend of an aging population, with Alzheimer’s disease (AD) being a leading neurodegenerative disorder characterized by memory loss, dementia, and cognitive decline. Despite extensive research, current treatments for AD remain largely symptomatic and have had limited success in halting disease progression, thereby shifting attention toward glial cells as promising therapeutic targets due to their emerging roles in AD pathogenesis. Astrocytes are involved in both beneficial and pathological processes in AD, such as cytokine secretion, Aβ removal, metabolic support, and tau pathology, with deficiency resulting in neuroinflammation and excitotoxicity. Microglia have dual functions in AD by phagocytosing amyloid plaques and limiting tau spread in initial phases but may develop a pro-inflammatory, neurodegenerative phenotype with progression of the disease. Oligodendrocytes and their precursors are involved in Aβ generation and myelin homeostasis, and their disturbance is responsible for white matter lesions and cognitive impairment, though their exact mechanisms are less clear. This review also examines emerging therapeutic strategies targeting glial cells, including modulating TREM2 pathways and novel drug candidates. These methods highlight the therapeutic value of the glial cells and provide valuable leads for furthering the treatment of AD by elucidating their changing roles in the course of the disease.
{"title":"Glial Cells in Alzheimer’s Disease: Pathogenic Mechanisms and Therapeutic Frontiers","authors":"Moumita Sil, Nabanita Mukherjee, Ishita Chatterjee, Ankita Ghosh, Arunava Goswami","doi":"10.1007/s12031-025-02379-8","DOIUrl":"10.1007/s12031-025-02379-8","url":null,"abstract":"<div><p>The rising incidence of brain diseases parallels the global trend of an aging population, with Alzheimer’s disease (AD) being a leading neurodegenerative disorder characterized by memory loss, dementia, and cognitive decline. Despite extensive research, current treatments for AD remain largely symptomatic and have had limited success in halting disease progression, thereby shifting attention toward glial cells as promising therapeutic targets due to their emerging roles in AD pathogenesis. Astrocytes are involved in both beneficial and pathological processes in AD, such as cytokine secretion, Aβ removal, metabolic support, and tau pathology, with deficiency resulting in neuroinflammation and excitotoxicity. Microglia have dual functions in AD by phagocytosing amyloid plaques and limiting tau spread in initial phases but may develop a pro-inflammatory, neurodegenerative phenotype with progression of the disease. Oligodendrocytes and their precursors are involved in Aβ generation and myelin homeostasis, and their disturbance is responsible for white matter lesions and cognitive impairment, though their exact mechanisms are less clear. This review also examines emerging therapeutic strategies targeting glial cells, including modulating TREM2 pathways and novel drug candidates. These methods highlight the therapeutic value of the glial cells and provide valuable leads for furthering the treatment of AD by elucidating their changing roles in the course of the disease.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 3","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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