Journal of Molecular Neuroscience最新文献

{"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}

{"title":"Retraction Note: Picroside II Exerts a Neuroprotective Effect by Inhibiting the Mitochondria Cytochrome C Signal Pathway Following Ischemia Reperfusion Injury in Rats","authors":"Hongyan Zhang,&nbsp;Li Zhai,&nbsp;Tingting Wang,&nbsp;Shan Li,&nbsp;Yunliang Guo","doi":"10.1007/s12031-025-02319-6","DOIUrl":"10.1007/s12031-025-02319-6","url":null,"abstract":"","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":"143404266","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":"Neurodegeneration in Autism: A Study of Clusterin, Very Long-Chain Fatty Acids, and Carnitine","authors":"Esra Yurumez,&nbsp;Merve Cikili-Uytun,&nbsp;Banu Kaymak,&nbsp;Ozlem Dogan,&nbsp;Humeyra Hilal Ozturk,&nbsp;Beyza Nur Baysar-Kanoglu,&nbsp;Didem Behice Oztop","doi":"10.1007/s12031-024-02303-6","DOIUrl":"10.1007/s12031-024-02303-6","url":null,"abstract":"<div><p>The clinical identification of regression phenomena in ASD lacks specific biological or laboratory criteria and is often based on family history and highly subjective observations by clinicians. The present study aimed to investigate the potential role of plasma clusterin (CLU), very long-chain fatty acids (VLCFA), and carnitine as biomarkers of neurodegeneration in children with autism spectrum disorder (ASD) with and without regression. By exploring these biomarkers, we sought to provide insights into mitochondrial dysfunction, glial activation, and lipid metabolism, which may contribute to the pathophysiology of ASD and aid in the early diagnosis and intervention of regression phenomena in ASD. Ninety children aged 2–6 years were included: 30 with autism spectrum disorder (ASD), 30 with regressive ASD, and 30 healthy controls. Psychiatric assessments were conducted using DSM-5 criteria, CARS, ABC, RBS-R, and ASSQ scales. Regression in ASD was evaluated retrospectively using a modified ADI-R questionnaire. Fasting blood samples were collected, and plasma clusterin (CLU), VLCFA, and carnitine levels were measured. Statistical analyses were performed using MANOVA to assess the effect of group differences on dependent biochemical variables. Serum clusterin and carnitine levels showed no significant differences between groups. However, C22 VLCFA levels were significantly higher in both autism groups compared to controls (<i>p</i> = 0.04), with post hoc analysis indicating the difference between the non-regressive and control groups (<i>p</i> = 0.02). Serum carnitine was positively correlated with stereotypic behaviors subscale scores (<i>r</i> = 0.37, <i>p</i> = 0.004) and total scores (<i>r</i> = 0.35, <i>p</i> = 0.006) of RBS-R. Our study provides insights into the complexities of biomarker research in autism spectrum disorder (ASD), highlighting the challenges in identifying consistent biological markers for regression and non-regression phenotypes. Although no significant findings were observed, further biomarker studies are essential to distinguish possible endophenotypes, improve early diagnosis, and uncover potential therapeutic targets in ASD.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388682","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":"Biochemical Markers as Predictors of Health Outcomes in Autism Spectrum Disorder: A Comprehensive Systematic Review and Meta-analysis","authors":"Walaa Mohammedsaeed,&nbsp;Mohammed Alharbi","doi":"10.1007/s12031-024-02306-3","DOIUrl":"10.1007/s12031-024-02306-3","url":null,"abstract":"<div><p>Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an increasing prevalence worldwide, including in Saudi Arabia. Emerging evidence suggests that biochemical markers, such as oxidative stress indicators, neurotransmitter levels, and lipid profiles, play a significant role in ASD’s pathology and may also elevate cardiovascular and metabolic risks in affected individuals. This systematic review and meta-analysis synthesize current findings on these biomarkers, with a particular focus on the Saudi population, to elucidate their relationship with ASD pathology and associated health outcomes. Following the PRISMA guidelines, data from 41 studies on oxidative stress markers, neurotransmitters, lipid profiles, and immune markers were analyzed. Searches were conducted across major databases, including PubMed, Scopus, Web of Science, and Embase, and effect sizes were calculated using standardized mean differences with a 95% confidence interval. To further interpret the data, bioinformatics tools such as Reactome, Panther, and STRING were employed to analyze biomarker pathways. The results highlight a significant association between elevated oxidative stress and mitochondrial dysfunction in individuals with ASD, with profound effects on gastrointestinal and mitochondrial health. These biochemical abnormalities disrupt synaptic plasticity and drive chronic neuroinflammation, which impairs neurodevelopmental processes, contributing to the pathology of ASD. The meta-analysis reveals minimal heterogeneity (<i>I</i>² = 0.02%) and limited publication bias, supporting the reliability of these associations. The findings underscore the need for a multidisciplinary approach to ASD management in Saudi Arabia, emphasizing biomarker-based diagnostics and personalized treatment strategies. Future research directions include developing individualized diagnostic and therapeutic frameworks utilizing these biomarkers to enhance ASD-related health outcomes.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254418","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":"Impaired Mitochondrial Function and Ubiquitin Proteasome System Activate α-Synuclein Aggregation in Zinc-Induced Neurotoxicity: Effect of Antioxidants","authors":"Garima Singh,&nbsp;Namrata Mittra,&nbsp;Chetna Singh","doi":"10.1007/s12031-024-02293-5","DOIUrl":"10.1007/s12031-024-02293-5","url":null,"abstract":"<div><p>Impairment in mitochondrial function and ubiquitin–proteasome system (UPS) and alpha-synuclein (α-Syn) aggregation are implicated in Zn-induced neurotoxicity. A link among these events leading to Zn-induced neurotoxicity is not yet properly deciphered. Therefore, the study intended to check the existence of a crosstalk between the mitochondria and UPS and its further link to α-Syn aggregation. The study also aimed to investigate the efficacy of tempol, a SOD mimetic and silymarin, a natural antioxidant, against Zn-induced alterations in animals and differentiated cells. Zn reduced the locomotor activity, dopamine content and tyrosine hydroxylase (TH) expression in the exposed animals. Zn augmented the levels of mitochondrial reactive oxygen species, α-Syn and protein-ubiquitin conjugates. Mitochondrial membrane potential, adenosine triphosphate (ATP) production, UPS-associated enzymatic activities and levels of UPS subunits (SUG-1 and β-5) were attenuated in Zn-exposed animals. While Zn augmented the expression of heat shock protein 110 (HSP110), peroxisome proliferator-activated receptor-gamma coactivator<i>-</i>1 alpha (PGC-1α) and Parkin translocation, the mitochondrial PTEN-induced kinase-1 (PINK-1) level was attenuated. In addition to tempol and silymarin, a mitochondrial permeability transition pore inhibitor, cyclosporine A, also alleviated the Zn-induced changes in animals. Similar trends in a few parameters were also observed in the differentiated human neuroblastoma SH-SY-5Y cells. Besides, UPS inhibitor, MG132, enhanced Zn-induced UPS impairment, protein aggregation and mitochondrial dysfunction in differentiated cells. These results suggest that mitochondrial dysfunction triggers UPS impairment or vice versa that elevates α-Syn aggregation and consequent neuronal death. Furthermore, tempol and silymarin ameliorate the mitochondrial and UPS impairments and α-Syn aggregation thereby providing protection from Zn-induced neurotoxicity.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143108344","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}