Journal of Molecular Neuroscience最新文献

{"title":"Insights Into the Therapeutic Potential of SIRT1-modifying Compounds for Alzheimer’s Disease: A Focus on Molecular Mechanisms","authors":"Dhyauldeen Aftan AlHayani,&nbsp;Aziz Kubaev,&nbsp;Subasini Uthirapathy,&nbsp;Viralkumar Mandaliya,&nbsp;Suhas Ballal,&nbsp;Rishiv Kalia,&nbsp;Renu Arya,&nbsp;Baneen C. Gabble,&nbsp;Mohammed Qasim Alasheqi,&nbsp;Abed J. Kadhim","doi":"10.1007/s12031-025-02324-9","DOIUrl":"10.1007/s12031-025-02324-9","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, significantly impacting patients’ quality of life. Recent studies have highlighted the roles of sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, in regulating various biological pathways associated with AD pathology, including amyloid-beta metabolism, tau hyperphosphorylation, and neuroinflammation. This review focuses on the therapeutic potential of synthetic and natural compounds that modulate SIRT1 levels, emphasizing their molecular mechanisms of action. We explore a range of SIRT1-modifying agents, including polyphenols such as resveratrol, as well as synthetic analogs and novel pharmaceuticals that aim to enhance SIRT1 activity. Additionally, we discuss emerging innovative therapies, including pharmacological agents that improve SIRT1 signaling through mechanisms like photobiomodulation and nutritional interventions. These compounds not only target SIRT1 but also integrate into broader metabolic and neuroprotective pathways, presenting a promising approach to ameliorating AD symptoms. By elucidating the intricate interactions between SIRT1-modifying compounds and their effects on AD pathology, this review aims to advance the understanding of potential therapeutic strategies that could delay or prevent the progression of AD.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489553","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}

{"title":"Malformations of Core M3 on α-Dystroglycan Are the Leading Cause of Dystroglycanopathies","authors":"Wessam Sharaf-Eldin","doi":"10.1007/s12031-025-02320-z","DOIUrl":"10.1007/s12031-025-02320-z","url":null,"abstract":"<div><p>Dystroglycanopathies (DGPs) are a group of autosomal recessive neuromuscular diseases with significant clinical and genetic heterogeneity. They originate due to defects in the O-mannosyl glycosylation of α-dystroglycan (α-DG), a prominent linker between the intracellular cytoskeleton and the extracellular matrix (ECM). Fundamentally, such interactions are crucial for the integrity of muscle fibers and neuromuscular synapses, where their defects are mainly associated with muscle and brain dysfunction. To date, biallelic variants in 18 genes have been associated with DGPs, where the underlying cause is still undefined in a significant proportion of patients. Glycosylation of α-DG generates three core motifs where the core M3 is responsible for interaction with the basement membrane. Consistently, all gene defects that corrupt core M3 maturation have been identified as causes of DGPs. <i>POMGNT1</i> which stimulates the generation of core M1 is also associated with DGPs, as it plays a central role in core M3 processing. Other genes involved in the glycosylation of α-DG seem unrelated to DPGs. The current review illustrates the <i>O</i>-mannosylation pathway of α-DG highlighting the functional properties of related genes and their contribution to the progression of DPGs. Different classes of DPGs are also elaborated characterizing the clinical features of each distinct type and phenotypes associated with each single gene. Finally, current therapeutic approaches with favorable outcomes are addressed. Potential achievements of preclinical and clinical studies would introduce effective curative therapies for this group of disorders in the near future.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02320-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489554","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}

{"title":"Effect of Interaction of ATG7 and Plasma Metal Concentrations on Cognitive Impairment in Rural China","authors":"Xu Tang,&nbsp;Jiejing Cao,&nbsp;Jiansheng Cai,&nbsp;Xiaoting Mo,&nbsp;Yanfei Wei,&nbsp;Kailian He,&nbsp;Zeyan Ye,&nbsp;Yu Jian Liang,&nbsp;Linhai Zhao,&nbsp;Lidong Qin,&nbsp;You Li,&nbsp;Jian Qin,&nbsp;Zhiyong Zhang","doi":"10.1007/s12031-025-02322-x","DOIUrl":"10.1007/s12031-025-02322-x","url":null,"abstract":"<div><p>The objective of this study is to explore the association of plasma metal concentrations with impaired cognitive function in different genotypes of ATG7 using multiple models. A cross-sectional survey was conducted in rural China among 994 individuals aged 30 years or older. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Genetic analysis focused on two single-nucleotide polymorphisms (SNPs) in the autophagy-related gene ATG7 (rs2606757 and rs8154). Plasma concentrations of metals were quantified using inductively coupled plasma mass spectrometry. Restricted cubic splines were used to explore the association between serum metal concentration and the occurrence of mild cognitive impairment in individuals with various genotypes. Bayesian Kernel Machine Regression (BKMR) models were used to explore the interactions between individual metals. In a restricted cubic spline model, there is a nonlinear relationship between plasma concentration of Cd and the occurrence of cognitive impairment in individuals carrying the AA (<i>P</i> of Nonlinear = 0.008) and AT (<i>P</i> of Nonlinear = 0.007) genotypes at the rs2606757. However, in people carrying the TT genotype at the rs2606757 locus, the concentration of metals in plasma was not significantly associated with cognitive impairment (<i>P</i> of Nonlinear = 0.534). The results of the BKMR model are consistent with those of the restricted cubic spline model. The TT genotype at rs2606757 in ATG7 appears to confer greater cognitive resilience against Cd-induced cognitive damage. These findings highlight the importance of considering gene-environment interactions in the context of cognitive impairment and suggest potential avenues for preventing cognitive decline in individuals exposed to Cd. Further research is needed to elucidate the precise mechanisms underlying these interactions.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475261","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}

{"title":"SOX10-Mediated Regulation of Enteric Glial Phenotype in vitro and its Relevance for Neuroinflammatory Disorders","authors":"Madlen Kunke,&nbsp;Meike Kaehler,&nbsp;Sebastien Boni,&nbsp;Katja Schröder,&nbsp;Alicia Weier,&nbsp;Rittika Chunder,&nbsp;Stefanie Kuerten,&nbsp;Martina Böttner,&nbsp;Ingolf Cascorbi,&nbsp;Michel Neunlist,&nbsp;Thilo Wedel,&nbsp;Ralph Lucius,&nbsp;François Cossais","doi":"10.1007/s12031-025-02321-y","DOIUrl":"10.1007/s12031-025-02321-y","url":null,"abstract":"<p>The transcription factor SOX10 is a key regulator of myelinated glial cell phenotype and function, with a known role in multiple sclerosis (MS). SOX10 is also expressed in enteric glial cells (EGC) within the gut, yet its regulatory functions in EGC remain poorly understood. This study aimed to identify SOX10 target genes that influence EGC phenotype and may have implications for MS. An EGC cell line was established for doxycycline-inducible SOX10 overexpression. Impact of SOX10 overexpression on EGC phenotype was assessed by genome-wide expression analysis and results were validated via RT-qPCR and western blot. Data were compared with SOX10 ChIP-seq and transcriptomic datasets from MS patients to identify pan-glial SOX10 target genes potentially linked to neuroinflammatory disorders. SOX10 overexpression was associated with ectopic upregulation of genes related to myelin regulation and glial differentiation, as evidenced by increased PLP1 expression at mRNA and protein levels. Comparison to ChIP-seq and MS datasets highlight SOX10 target genes, including <i>PLP1</i>, <i>RNF130</i>, <i>NES</i> and <i>APOD</i> potentially involved in central and peripheral manifestations of MS pathology. Our findings support a cell-specific regulation of EGC phenotype through SOX10 expression level and identify SOX10-regulated genes relevant to EGC function. This research advances the understanding of EGC diversity and provide information about glial cells targeting in neuroinflammatory disorders.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02321-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455660","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}

{"title":"Chitinase-3 Like-Protein-1 Signature in Neurological Disorders: Emphasis on Stroke","authors":"Khiany Mathias,&nbsp;Richard Simon Machado,&nbsp;Naíla Maciel Andrade,&nbsp;Natalia Piacentini,&nbsp;Carla Damasio Martins,&nbsp;Josiane Somariva Prophiro,&nbsp;Fabricia Petronilho","doi":"10.1007/s12031-025-02311-0","DOIUrl":"10.1007/s12031-025-02311-0","url":null,"abstract":"<div><p>Chitinase-3 like-protein-1 (CHI3L1) is a protein involved in various pathological conditions, including infectious, allergic, metabolic, cardiovascular, and neurological diseases. In the central nervous system, glial cells, especially activated astrocytes, are the primary sources of CHI3L1 synthesis and secretion. In neurodegenerative diseases, such as Alzheimer's disease, elevated levels of CHI3L1 are correlated with greater cognitive decline and neuroinflammation. Regarding stroke, CHI3L1 is a relevant biomarker associated with an increased risk of adverse events and mortality, particularly in patients with elevated levels following the onset of symptoms. Overall, the presence of CHI3L1 may reflect disease severity and aid in predicting outcomes. This narrative review explores the potential role of CHI3L1 in neurological diseases, with an emphasis on stroke, and it may contribute to guiding the development of effective inhibitors, which could be an attractive therapeutic approach for treating this condition.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02311-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446384","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}

{"title":"Cdh23 Gene Mutation–Induced Vestibular Dysfunction in Mice: Abnormal Stereocilia Bundle and Otolith Development and Activation of p53/FoxO Signaling Pathway","authors":"Lihuan Tang,&nbsp;Yuancheng Wu,&nbsp;Kai Zhang,&nbsp;Daoli Xie,&nbsp;Xiaojing Kuang,&nbsp;Lan Wang,&nbsp;Zehua Sun,&nbsp;Ruishuang Geng,&nbsp;Juan Hu,&nbsp;Yan Sun,&nbsp;Tihua Zheng,&nbsp;Bo Li,&nbsp;Qingyin Zheng","doi":"10.1007/s12031-025-02318-7","DOIUrl":"10.1007/s12031-025-02318-7","url":null,"abstract":"<div><p>Vestibular dysfunction (VD) is increasingly acknowledged as a significant contributor to falls and deterioration in health. <i>Cadherin 23</i> (<i>Cdh23</i>) serves as an essential protein responsible for facilitating the mechanical transduction processes in hair cells, and variations in this gene have been recognized as possible factor to auditory impairments and VD. The gene <i>Cdh23</i> encodes glycoproteins that play a role in cell adhesion and are crucial for the development of stereocilia bundles. In this research, we generated CDH23 functional null mice (<i>Cdh23</i>^{<i>V2J2/V2J2</i>}). Here, our findings indicated that <i>Cdh23</i>^{<i>V2J2/V2J2</i>} mice exhibited weakened balance and coordination abilities, characterized by rotation and head nodding movements. The development of stereocilia and otoliths was abnormal in these mice. Scanning electron microscopy (SEM) analysis revealed abnormal changes in the arrangement and length of stereocilia bundles in <i>Cdh23</i>^{<i>V2J2/V2J2</i>} mice compared to wild-type mice. The abnormal alterations of otolith shape in <i>Cdh23</i>^{<i>V2J2/V2J2</i>} mice also were observed, which was smaller in saccules but larger in utricles. Furthermore, we also observed that the number of vestibular hair cells (VHCs) decreased in <i>Cdh23</i>^{<i>V2J2/V2J2</i>} mice, along with significant activation of the p53 and FoxO signaling pathways at postnatal day 56 (P56). This study elucidates potential mechanisms, histopathological features, and resultant genomic alterations associated with VD in <i>Cdh23</i>^{<i>V2J2/V2J2</i>} mice, thereby establishing a scientific foundation for prospective vestibular rehabilitative interventions.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438613","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}

{"title":"Identification of Key Genes and Immune Characteristics of SASP in Acute Ischemic Stroke","authors":"Hanlu Cai,&nbsp;Huixue Zhang,&nbsp;Guanghao Xin,&nbsp;Shanshan Peng,&nbsp;Fanfan Xu,&nbsp;Nan Zhang,&nbsp;Yichen Li,&nbsp;Wei Zhang,&nbsp;Ying Li,&nbsp;Yingjie Ren,&nbsp;Yu Wang,&nbsp;Zhaojun Liu,&nbsp;Xiaotong Kong,&nbsp;Lihua Wang","doi":"10.1007/s12031-025-02312-z","DOIUrl":"10.1007/s12031-025-02312-z","url":null,"abstract":"<div><p>The senescence-associated secretory phenotype (SASP) is a key mechanism through which senescent cardiovascular cells contribute to plaque formation, instability, and vascular remodeling. However, the correlation between SASP and acute ischemic stroke (AIS), particularly its immune inflammation characteristics, remains underexplored and requires further elucidation. We downloaded the AIS database from the GEO database and obtained SASP genes from the SASP Atlas and related literature. Using two machine learning algorithms, we identified five hub genes. Unsupervised cluster analysis was performed on patients with AIS and DEGs separately to identify distinct gene clusters, which were then analyzed for immune characteristics. We then explored the related biological functions and immune properties of the hub genes by using various algorithms (GSEA, GSVA, and CIBERSORT). Principal component analysis (PCA) was used to generate SASP-related gene scores based on the expression of hub genes. A logistic regression algorithm was employed to establish an AIS classification diagnosis model based on the hub genes. Peripheral venous blood was collected for validation using real-time quantitative PCR (RT-qPCR). We identified five hub genes using two machine learning algorithms and validated them with RT-qPCR. Gene cluster analysis revealed two distinct clusters, SASP-related gene cluster B and differentially expressed gene cluster B, indicating that the acute AIS samples had more severe immune inflammatory response and a higher risk of disease deterioration. We constructed a gene-drug regulatory network for PIN1 and established an AIS diagnostic model and nomogram using a logistic regression algorithm. This study explored the gene expression, molecular patterns, and immunological characteristics of SASP in patients with AIS using bioinformatic methods. It provides a theoretical basis and research direction for identifying new diagnostic markers for AIS, understanding the molecular mechanism of thrombosis, and improving the classification, diagnosis, treatment, and prognosis of AIS.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423181","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}

{"title":"Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes","authors":"Gengxin Lu,&nbsp;Junyu Wu,&nbsp;Zhihui Zheng,&nbsp;Zhezhi Deng,&nbsp;Xue Xu,&nbsp;Xintian Li,&nbsp;Xiaoqiu Liang,&nbsp;Weiwei Qi,&nbsp;Shifeng Zhang,&nbsp;Yuemin Qiu,&nbsp;Minping Li,&nbsp;Junjie Guo,&nbsp;Haiwei Huang","doi":"10.1007/s12031-024-02302-7","DOIUrl":"10.1007/s12031-024-02302-7","url":null,"abstract":"<div><p>Radiation brain injury (RBI) is a complication of cranial tumor radiotherapy that significantly impacts patients' quality of life. Astrocyte-secreted vascular endothelial growth factor (VEGF) disrupts the blood–brain barrier (BBB) in RBI. However, further studies are required to elucidate the complex molecular mechanisms involved. Reactive oxygen species (ROS) are closely linked to VEGF pathway regulation, with excessive ROS potentially disrupting this pathway. Mitochondria, the primary ROS-producing organelles, play a crucial role under irradiation. Our findings suggest that irradiation activates astrocytes with altered polarity, generating both cellular and mitochondrial ROS. Concurrently, mitochondrial morphology and function are disrupted, leading to defective mitophagy and an accumulation of damaged mitochondria, which further exacerbates ROS damage. Urolithin A (UA) is a natural activator of mitophagy. We found that UA promoted mitophagy in irradiated astrocytes, reduced cellular and mitochondrial ROS, restored mitochondrial morphology and function, reversed VEGF overexpression, and attenuated the disruption of endothelial tight junction proteins in endothelial cells cultured with irradiated astrocyte supernatants. In conclusion, our study identifies a connection between impaired mitophagy and VEGF overexpression in radiation-induced astrocytes. We also demonstrated UA may serve as a therapeutic strategy for protecting the tight junction protein in RBI by enhancing mitophagy, reducing ROS accumulation, and downregulating VEGF expression.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143430917","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}

{"title":"Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients","authors":"Yara Al Ojaimi,&nbsp;Nicolas Vallet,&nbsp;Audrey Dangoumau,&nbsp;Débora Lanznaster,&nbsp;Clement Bruno,&nbsp;Antoine Lefevre,&nbsp;Samira Osman,&nbsp;Camille Dupuy,&nbsp;Patrick Emond,&nbsp;Patrick Vourc’h,&nbsp;Philippe Corcia,&nbsp;Zuzana Krupova,&nbsp;Charlotte Veyrat-Durebex,&nbsp;Hélène Blasco","doi":"10.1007/s12031-025-02315-w","DOIUrl":"10.1007/s12031-025-02315-w","url":null,"abstract":"<div><p>The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423253","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}

{"title":"Navigating Uncertainty: Assessing Variants of Uncertain Significance in the CDKL5 Gene for Developmental and Epileptic Encephalopathy Using In Silico Prediction Tools and Computational Analysis","authors":"Özlem Yalçın Çapan","doi":"10.1007/s12031-024-02299-z","DOIUrl":"10.1007/s12031-024-02299-z","url":null,"abstract":"<div><p>Mutations in the CDKL5 gene are associated with developmental and epileptic encephalopathy (DEE), a severe disorder characterized by developmental delay and epileptic activity. In genetic analyses of DEEs, variants classified as pathogenic confirm the diagnosis of the disease while Variants of Uncertain Significance (VUS) remain in a gray area due to insufficient evidence. This study aimed to optimize the interpretation of VUS in the CDKL5 gene by evaluating the performance of 22 in silico prediction tools using 186 known pathogenic or benign missense variants from the ClinVar database. The best-performing tools were then applied to analyze CDKL5 VUS variants, complemented by the evaluation of evolutionary conservation, structural analyses, and molecular dynamics simulations to assess their impact on protein structure and function. The results identified SNPred as the most reliable tool, achieving 100% accuracy, sensitivity, and specificity. Other high-performing tools, including ESM-1v, AlphaMissense, EVE, and ClinPred, demonstrated over 98% accuracy. Among 44 CDKL5 VUS variants evaluated, 20 were initially classified as pathogenic by these tools. However, further evaluation using stringent criteria—incorporating conservation scores, structural disruptions identified by Missense3D and PyMol, and molecular dynamics simulation results—led to the reclassification of 8 VUS variants as “potentially pathogenic” and the remaining 12 as “variants with conflicting data”. This comprehensive approach provides a robust framework for the classification of VUS in the CDKL5 gene, offering critical insights for accurate diagnosis and treatment strategies in DEE. These findings will serve as a valuable resource for clinicians and geneticists in resolving the diagnostic ambiguity associated with VUS.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404087","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}