Neurobiology of Disease最新文献

{"title":"Expression of concern: \"Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons\" [Neurobiology of Disease, Volume 41 (2011) Pages 209-218].","authors":"","doi":"10.1016/j.nbd.2025.107085","DOIUrl":"10.1016/j.nbd.2025.107085","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"215 ","pages":"107085"},"PeriodicalIF":5.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating mitochondrial components and metabolic and inflammatory markers in Charcot-Marie-Tooth type 2B.","authors":"Giulia Girolimetti, Federico Marini, Riccardo Calvani, Hélio José Coelho-Júnior, Jacopo Gervasoni, Lavinia Santucci, Stefano Tozza, Fiore Manganelli, Paola Saveri, Davide Pareyson, Emanuele Marzetti, Cecilia Bucci, Anna Picca, Flora Guerra","doi":"10.1016/j.nbd.2025.107051","DOIUrl":"10.1016/j.nbd.2025.107051","url":null,"abstract":"<p><p>Charcot-Marie-Tooth type 2B (CMT2B) is a rare inherited neuropathy caused by mutations in the RAB7A gene. Altered mitochondrial dynamics and late endosome trafficking contribute to CMT2B pathophysiology. In this case-control study, we quantified levels of circulating cell-free mtDNA (ccf-mtDNA), mitochondrial proteins secreted within mitochondria-derived vesicles (MDVs), and metabolic and inflammatory markers in biofluids of individuals with CMT2B (n = 5) and healthy controls (n = 4). ccf-mtDNA was quantified in serum by droplet digital PCR. MDVs were purified by immunoprecipitation and analyzed by Western blotting. A panel of 27 inflammatory markers was assayed in serum by multiplex immunoassay. Forty-four amino acids and derivatives were quantified in serum and urine by ultraperformance liquid chromatography/mass spectrometry (UPLC/MS). Fourteen long-chain fatty acids and asymmetric dimethyl arginine (ADMA) were measured in serum by UPLC/MS. Analysis of variance - simultaneous component analysis models were built to explore differences in metabolic and inflammatory markers between cases and controls. Mann-Whitney U test was used to compare ccf-mtDNA levels between groups. Spearman's correlation analysis was applied to explore the relationship between markers of inflammation, endothelial dysfunction, and fatty acid metabolism. CMT2B participants had higher levels of ADMA as well as of interleukin (IL)-1b, IL-8, IL-9, IL-13, eotaxin, and most fatty acids than controls. Serum levels of 1- and 3-methylhistidine, alfa- and beta-aminobutyric acid, asparagine, glycine, threonine, and fibroblast growth factor were lower in CMT2B samples than in controls. No significant differences were observed for ccf-mtDNA levels between groups, while differences in MDV content were identified between participants with CMT2B and controls. Among the metabolic markers, ADMA was the most discriminant biomolecule distinguishing CMT2B participants from controls and showed a positive correlation with some fatty acids. Collectively, these findings suggest that CMT2B may be associated with altered endosomal trafficking and mitochondrial and endothelial dysfunction.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107051"},"PeriodicalIF":5.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the dual regulatory systems: Contemporary insights into the lateral habenula and rostromedial tegmental nucleus physiology.","authors":"Juntao Cui, Junliang Qian, Jun Wang, Limin Shi","doi":"10.1016/j.nbd.2025.107049","DOIUrl":"10.1016/j.nbd.2025.107049","url":null,"abstract":"<p><p>The lateral habenula (LHb) and the rostromedial tegmental nucleus (RMTg) are critical brain structures involved in reward processing, aversive signaling, and mood regulation. Recent research has uncovered significant progress in understanding their physiological functions, neural circuits, and implications in neuropsychiatric disorders. By integrating signals from the limbic system and projecting into the midbrain monoaminergic system, the LHb encodes negative reward prediction error and mediates behaviors associated with depressive as well as stress response. Its overactivation can inhibit dopamine release, resulting in anhedonia. As the main downstream target of LHb, the RMTg exerts inhibitory control over dopaminergic neurons in the ventral tegmental area (VTA) via γ-aminobutyric acid (GABA), and participates in reward inhibition, addiction withdrawal and hyperalgesia regulation. The LHb activates GABAergic neurons within the RMTg through glutaminergic projection, thereby inhibiting dopamine release in the VTA neurons. This neuronal circuitry is critically involved in the pathophysiological mechanisms of depression, addiction and other neuropsychiatric disorders‌. Here, we reviewed the anatomical features and molecular markers of both LHb and RMTg along with their inputs, outputs and physiological functions of LHb and RMTg. This research is of great significance for understanding the neural mechanisms underlying neuropsychiatric diseases.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107049"},"PeriodicalIF":5.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new serological autoantibody signature associated with multiple sclerosis.","authors":"Houari Abdesselem, Alberto de la Fuente, Ilham Bensmail, Israa E Elbashir, Diana Anuar, Tan Ti-Myen, Bermet Abylova, Jonathan M Blackburn, Rayaz A Malik, Ioannis N Petropoulos","doi":"10.1016/j.nbd.2025.107116","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107116","url":null,"abstract":"<p><p>The role of autoantibodies in the pathogenesis of Multiple Sclerosis (MS) remains incompletely understood. In this study, we analysed serum samples from a cohort of MS patients in Qatar using high-throughput KoRectly Expressed (KREX) immunome protein-array technology. Compared to healthy controls, MS patients showed significantly altered autoantibody responses to 129 proteins, with a notable enrichment in autoantibodies targeting antiviral immune response-related proteins and oligodendrocyte marker SOX-10. Machine learning analysis identified a distinct molecular signature comprising 17 differentially expressed autoantibodies, including those against MX1, ISG20, MAX, SUFU, NR1H2, HMGN5, and EPHA10. Among these, autoantibodies against MX1-a key effector in the interferon-alpha/beta signalling pathway-showed the most pronounced increase, with nearly a threefold elevation in MS patients. While MX1 has previously been implicated in MS, this is the first report of autoantibody reactivity against the protein, suggesting a potential role in disease onset and progression. These findings support a link between antiviral immune responses and MS pathophysiology and offer a promising blood-based autoantibody signature that could inform future diagnostic and therapeutic strategies.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107116"},"PeriodicalIF":5.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered APP trafficking drives amyloidogenic processing in primary neurons from the App^NL-F knock-in mouse model of Alzheimer's disease.","authors":"Yang Yu, Robin Ziyue Zhou, Per Nilsson, Bengt Winblad, Lars O Tjernberg, Sophia Schedin-Weiss","doi":"10.1016/j.nbd.2025.107129","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107129","url":null,"abstract":"<p><p>Self-assembly of the 42-residue long amyloid β-peptide (Aβ42) into neurotoxic aggregates - eventually leading to formation of amyloid plaques - is a key event in Alzheimer's disease (AD) pathogenesis. Still, the intracellular mechanisms leading to Aβ42 formation and aggregation in neurons are poorly defined. Here, we used the App^NL-F knock-in mouse model to analyze the effect of Aβ42-induced pathology on the subcellular location of the Aβ precursor protein (APP), its C-terminal fragments (CTFs) and Aβ42 in primary neurons. Stimulated emission depletion (STED) microscopy was used to obtain super-resolution and enable colocalization analysis. APP/CTF levels were to a high extent found in clathrin-coated vesicles in the perinuclear region in soma in both wild-type and App^NL-F neurons and significantly increased in early endosomes in neurites. In distal axons, increased colocalization of APP/CTF with the synaptic vesicle protein synaptophysin was observed. Western blotting showed a three-fold decrease in mature/immature APP in App^NL-F neurons, and ELISA showed a 2.7 and 7.2-fold increase in intra- and extracellular Aβ42 levels, respectively. Interestingly, LAMP1-positive vesicles were larger in App^NL-F neurons than in wild-type neurons. Thus, processing of APP and axonal transport of APP/CTFs is increased in App^NL-F neurons, resulting in enhanced levels of the immediate Aβ precursor (CTFβ) at the presynapse. Hence, an increase in CTFβ levels at sites with high γ-secretase activity leads to increased formation and secretion of Aβ42. This, in turn, results in enhanced re-uptake of Aβ42 and enlarged Aβ42-containing late endosomes/lysosomes in soma, causing toxic downstream effects.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107129"},"PeriodicalIF":5.6,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single nucleus RNA sequencing unveils relationship between microglia and endothelial cells in mixed Alzheimer's disease and vascular pathology.","authors":"Oluwatosin A Olayinka, Nicholas O'Neill, Jenny A Empawi, Payton Bock, Junming Hu, Hannah Rickner, Melissa Wong, Thor D Stein, Benjamin Wolozin, Lindsay A Farrer, Xiaoling Zhang","doi":"10.1016/j.nbd.2025.107128","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107128","url":null,"abstract":"<p><p>Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of cell type-specific transcriptional profiles. We evaluated differential gene expression using snRNAseq data generated from hippocampal region tissue donated by 11 Boston University Alzheimer's Disease Research Center (BU-ADRC) participants with neuropathologically confirmed Alzheimer's disease (AD) with or without co-existing pathology (AD only = 3, AD+vascular disease (Vas) = 6, AD+Lewy body disease (LBD) = 2). Expression of 19,893 genes was compared between AD+Vas and other AD groups for each cell type. Co-expression modules were identified in a set of 174 bulk RNAseq hippocampal samples from BU-ADRC. Modules enriched in differentially expressed genes (DEGs) were identified using Fisher's exact tests. The overlap between DEGs and co-expression modules was incorporated into quantitative gene set analysis. AD+Vas subjects showed decreased expression of genes related to immune activation in microglia (t = -2.67, p = 2.72 × 10^-2). Expression of these genes was negatively associated with expression of receptors P2RY12 and CX3CR1 (r = -0.87, p = 1.70 × 10^-2), which have been linked to microglial migration and activation, respectively. Expression of genes that negatively regulate angiogenesis in endothelial cells was decreased (t = -4.84, p = 1.49 × 10^-3) and associated with expression of the microglial activation genes in the BU-ADRC dataset (r = 0.68, p = 1.63 × 10^-2). This association and the finding of upregulation of P2RY12 in AD+Vas samples were replicated in 393 ROSMAP Study dorsolateral prefrontal cortex snRNAseq samples (r = 0.34, p = 8.37 × 10^-12 and z = 5.82, p_FDR = 8.73 × 10^-6, respectively). In summary, we found an expression profile in brain tissue from individuals with AD+Vas pathology that is associated with reduced activation and increased migration in microglia and angiogenesis in endothelial cells.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107128"},"PeriodicalIF":5.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut transit and gut microbiome changes occur prior to the onset of motor impairment in a mouse model of Machado-Joseph disease.","authors":"Vasilisa Zvyagina, Andrea Kuriakose, Ignacio Simó, Julia Y Kam, Prapti Chakraborty, Katherine J Robinson, Anastasiya Potapenko, Maxinne Watchon, Ian T Paulsen, Hasinika K A H Gamage, Angela S Laird","doi":"10.1016/j.nbd.2025.107121","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107121","url":null,"abstract":"<p><p>We previously identified microbial shifts prior to the onset of motor and neurological symptoms within a mouse model of the fatal neurodegenerative disease Machado-Joseph disease (MJD). Here, we aimed to explore possible mechanisms contributing to these changes within the microbiome-gut-brain axis, and whether it preceded or followed central neurodegeneration. We report that pre-symptomatic male MJD mice present with significantly different microbiome communities as early as 5-weeks-old. Furthermore, we show that male MJD mice have faster total gut transit times by 9-weeks-old, prior to signs of impaired motor function by 11-weeks-old. To elucidate whether these microbial and colonic functional changes are due to the presence of pathological and morphological changes in the gut, we examined the gut of pre- and early symptomatic MJD mice for formation of ataxin-3 protein aggregates and morphological changes relative to proteinopathy in the brain. Interestingly, we observed ataxin-3 aggregates within the brains of pre-symptomatic MJD mice, with aggregates present in male MJD mice from 5-weeks-of-age, an earlier timepoint than previously reported, coinciding with changes within the microbiome. However, we observed no ataxin-3 protein aggregates and no changes in enteric neuron populations or morphology within the gut. Analysis of endocrine factors involved in gut motility and inflammatory markers within the small intestine of 13-week-old males revealed increased expression of genes encoding cholecystokinin (Cck), ghrelin (Ghrl), heme oxygenase (Ho1), interleukin-1 beta (Il1b), and decreased inducible nitric oxide synthase (Nos2). Together, we demonstrate for the first time that colonic dysfunction occurs after gut microbiome changes, but prior to the onset of motor impairments in male MJD mice. Our work suggests that whilst proteinopathy or morphological changes within the gut may not be involved in these changes, inflammation and related endocrine changes could have a role in the interplay between the gut and brain during MJD development, warranting further investigation.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107121"},"PeriodicalIF":5.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A meta-analysis of genetic variant pathogenicity and sex differences in UBQLN2-linked amyotrophic lateral sclerosis and frontotemporal dementia.","authors":"Kyrah M Thumbadoo, Laura R Nementzik, Molly E V Swanson, Birger V Dieriks, Michael Dragunow, Richard L M Faull, Maurice A Curtis, Ian P Blair, Garth A Nicholson, Kelly L Williams, Emma L Scotter","doi":"10.1016/j.nbd.2025.107127","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107127","url":null,"abstract":"<p><p>Ubiquilin 2, encoded by the X-linked UBQLN2 gene, is a ubiquitin-binding quality control protein. Pathogenic UBQLN2 genetic variants cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS/FTD), however, clinical phenotypes from these variants show striking inter- and intra-familial heterogeneity. Further, there are many UBQLN2 variants whose significance to disease is uncertain. Here, we examine the pathogenic potential of UBQLN2 variants reported in individuals with ALS/FTD and their non-symptomatic relatives. Meta-analysis from 27 published studies identified 186 affected individuals and 51 asymptomatic carriers, each harbouring one of 43 unique UBQLN2 coding variants. Features of identified variants, including evolutionary conservation, minor allele frequencies, localisation to protein domains, and in silico predictions of pathogenicity were compiled. Per biological sex, clinical features were compared between UBQLN2 variants segregated by pathogenicity. Pathogenic UBQLN2 variants carriers, of which most are familial ALS cases, showed a sex-specific difference in age at onset wherein males developed disease on average 18.15 years prior to females (29.54 ± 11.9 versus 47.69 ± 13.4 years, p < 0.0001), with no change in disease duration (p = 0.2091). UBQLN2 variants of uncertain significance showed a bimodal distribution of onset age per sex suggesting a mixture of true benign and true pathogenic variants. In human brain tissue, two male UBQLN2 p.Thr487Ile (ALS-FTD and ALS) cases showed a greater burden of ubiquilin 2 aggregates than a related female case (ALS-FTD). These robust sex-specific differences in ALS/FTD presentation in carriers of pathogenic UBQLN2 variants may improve predictions of ALS/FTD risk in carriers, aiding in diagnosis and disease management.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107127"},"PeriodicalIF":5.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling central nervous system disorders in zebrafish: Novel insights into pathophysiology and therapeutic discovery.","authors":"Xin Meng, Lan Yang, Zi Liao, Feiyue Sun, Meng Su, Zhigang Mei","doi":"10.1016/j.nbd.2025.107123","DOIUrl":"10.1016/j.nbd.2025.107123","url":null,"abstract":"<p><p>Central nervous system (CNS) disorders present a profound global health burden, yet therapeutic progress is frequently impeded by their mechanistic complexity, the restrictive nature of the blood-brain barrier (BBB), and the limitations of traditional mammalian models. The zebrafish (Danio rerio) has emerged as a powerful vertebrate model system uniquely positioned to surmount these obstacles. Its genetic tractability and the conserved principles of its neurovascular development provide an unparalleled platform for dissecting complex disease pathways in vivo. The optical transparency of zebrafish larvae, in particular, enables real-time, high-resolution imaging of dynamic cellular processes, such as neuroinflammation and neurovascular unit dysfunction, offering mechanistic insights unattainable in other models. Furthermore, key physiological traits-including external fertilization for high-throughput screening and exceptional hypoxia tolerance for robust ischemic stroke modeling-make zebrafish an ideal tool for both fundamental research and preclinical drug discovery. This review synthesizes the pivotal contributions of the zebrafish model to our understanding of a wide spectrum of CNS disorders, and highlights its expanding role in accelerating the identification of novel therapeutic strategies.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107123"},"PeriodicalIF":5.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSC-derived glutamatergic neurons with pathogenic KCNQ2 variants display hyperactive bursting phenotypes.","authors":"Maria Sundberg, Carole Shum, Erika Norabuena, Nina R Makhortova, Cidi Chen, Lucy Yu, Emma V Wightman, Kristina Kim, Sang Yeon Han, Jennifer Howe, Annapurna Poduri, Elizabeth D Buttermore, Stephen W Scherer, Mustafa Sahin","doi":"10.1016/j.nbd.2025.107126","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107126","url":null,"abstract":"<p><p>Pathogenic variants in the KCNQ2 gene, which encodes a potassium channel subunit, are associated with neonatal seizures, epileptic encephalopathy, intellectual disability, and autism. Although the consequences of disrupted KCNQ2 channel function have been studied in the past, the detailed molecular mechanisms underlying the development of neurological phenotypes remain unclear, and neuronal models of specific patient variants are lacking. We generated patient-specific induced pluripotent stem cells (iPSCs) from fibroblasts from three individuals with distinct KCNQ2 pathogenic variants. We corrected the KCNQ2 variants using CRISPR-Cas9 editing to create isogenic controls and differentiated these iPSCs into glutamatergic neurons to study the effects of each variant on neuronal function. The three KCNQ2 variants were: 1) KCNQ2 c.875_877delTCCinsCCT, L292_L293delinsPF, 2) KCNQ2 c.766G > T, G256W, and 3) KCNQ2 c.821C > T, T274M. Our data revealed longer neurite outgrowth in two patient lines (T274M and G256W). Transcriptional profiling showed that all three KCNQ2 lines co-expressed genes enriched in synaptic transmission/signaling, cell adhesion, and GTPase signal transduction. Functional analyses of neuronal networks revealed increased burst duration in all three KCNQ2 lines compared with their isogenic controls. Furthermore, neurons from the L292_L293delinsPF and T274M lines displayed increased network connectivity associated with increased density of synaptic markers. Finally, we detected hyperexcitable neuronal networks in the G256W line with electrical stimulation of the neural networks on a high-density microelectrode array, and this phenotype was rescued with retigabine. These disease-related phenotypes for each of the KCNQ2 pathogenic variants can be used for drug screening to identify treatment options for the patients.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107126"},"PeriodicalIF":5.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}