Molecular Neurobiology最新文献

{"title":"SFRS8 Regulates Memory by Modulating RNA Splicing of Synaptic Genes.","authors":"Zeng Ding, Qiang Liu, Juan Zhang","doi":"10.1007/s12035-025-05036-8","DOIUrl":"https://doi.org/10.1007/s12035-025-05036-8","url":null,"abstract":"<p><p>SFRS8, a member of the serine and arginine-rich (SR) protein family, functions as a splicing factor and is highly expressed in the brain. Despite its abundance, its specific role in the brain has remained unclear. Here, we show that SFRS8 is critical for maintaining normal synaptic protein levels and synaptic density. Mechanistically, SFRS8 binds to SF3B3, a key component of the U2 snRNP complex, to regulate alternative RNA splicing. Specifically, SFRS8 regulates the association of Psd95 pre-mRNA with the U2 snRNP complex and subsequent exon 18 skipping in Psd95, thereby controlling PSD95 protein levels. Knockdown of SFRS8 in the hippocampus reduces synaptic protein expression, decreases dendritic spine density, and impairs memory in mice. Consistent with these in vivo findings, SFRS8 depletion in cultured neurons also leads to lower synaptic protein levels and reduced synaptic density. Taken together, our results demonstrate that SFRS8 regulates memory function in mice by modulating the alternative splicing and expression of synaptic genes through its interaction with SF3B3, a core component of the U2 snRNP complex.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151259","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":"The Impact of Maternal Obesity and Deprivation On Energy Metabolism, Oxidative Stress and Brain Antioxidant Defense in the Neurodevelopment of Offspring in the Short, Medium and Long Term.","authors":"Mariella Reinol Steiner, Aline Haas de Mello, Daniele Hendler Salla, Catarina Barbosa Chaves Bressan, Rayane Luiz Mendes, Mariana Pacheco de Oliveira, Larissa Espindola da Silva, Bruna Barros Fernandes, Igor Ramos Lima, Rubya Pereira Zaccaron, Gislaine Zilli Réus, Paulo Cesar Lock Silveira, Emílio Luiz Streck, Gislaine Tezza Rezin","doi":"10.1007/s12035-025-05070-6","DOIUrl":"https://doi.org/10.1007/s12035-025-05070-6","url":null,"abstract":"<p><p>The current global obesity epidemic is often associated with changes in dietary habits and lifestyle. Increasing evidence from both observational and experimental animal studies has highlighted the relationship between prenatal exposures and an increased predisposition to metabolic and cognitive disorders, as well as obesity in adulthood. In this study, we used a rodent model to investigate brain energy metabolism by assessing mitochondrial respiratory chain complexes I and II, along with oxidative stress markers (DCF) and antioxidant defenses (GSH and SOD), aiming to identify potential alterations in the central nervous system during offspring neurodevelopment. Our results demonstrated increased body weight and mesenteric fat accumulation in early life and adolescence, along with an imbalance in brain energy metabolism when maternal obesity and early-life stress (maternal deprivation) were combined. By exploring the complex interactions between gestational exposures and long-term behavioral and metabolic outcomes in an experimental model, our findings contribute to a better understanding of the developmental origins of health and disease.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136333","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":"Protein Structure-based FUS Mutational Subtypes Are Associated With Protein Mislocalization in Amyotrophic Lateral Sclerosis Patients.","authors":"Wanli Yang, Zhen Luo, Xuelin Tang, Jingyan Guo, Xi Chen, Yi Dong, Yi-Min Sun, Dongsheng Fan, Ke Xu, Yan Chen, Ming Zhang","doi":"10.1007/s12035-025-05085-z","DOIUrl":"https://doi.org/10.1007/s12035-025-05085-z","url":null,"abstract":"<p><p>The mislocalization of RNA-binding proteins (RBPs) from nucleus to cytoplasm and the formation of aggregates are hallmarks of neurodegeneration. Amyotrophic lateral sclerosis (ALS) disease-causing mutations in the fused in sarcoma (FUS) gene, encoding an RNA-binding protein, cluster at the C-terminal proline/tyrosine-nuclear localization signal (PY-NLS) domain, which is crucial for mediating nucleus-cytoplasm translocation by binding to Transportin-1. However, the mechanisms underlying heterogeneous protein mislocalization and age at onset (AAO) of ALS cases carrying FUS PY-NLS mutations remain unclear. Here, we screened FUS mutations in 416 ALS patients, and identified 12 patients carrying four FUS mutations at the p.R521 locus of PY-NLS domain (p.R521P, p.R521C, p.R521G, p.R521H), exhibiting highly variable AAO (20-56 years). AlphaFold-2 predicted protein structures classified FUS p.R521 mutants into alpha-helix containing (p.R521C, p.R521H) and alpha-helix disrupted (p.R521P, p.R521G) subgroups. Isothermal titration calorimetry experiment showed that the FUS alpha-helix disrupted subgroup had a reduced binding affinity with transportin-1, which is essential for mediating the nucleus-cytoplasm translocation. Furthermore, immunofluorescence in HEK-293 T and SH-SY5Y cells revealed more protein mislocalization in the FUS alpha-helix disrupted subgroup compared to the alpha-helix containing subgroup. FUS mislocalization status is also significantly associated with ALS AAO. Finally, the alpha-helix structure based FUS-ALS subgroups exhibited significantly different AAO (P = 0.036) in our cohort, but not in a Chinese cohort including published dataset. In summary, we showed highly diverse phenotypes in ALS patients with FUS R521 mutants, and implicated a link between genetic mutation related C-terminal structure with the status of FUS protein mislocalization.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143097","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":"Leveraging Alzheimer's Disease Omics to Identify Pleiotropic Genes Contributing to Neurodegeneration in Primary Open-Angle Glaucoma.","authors":"Paulina Tolosa-Tort, Andrew T DeWan","doi":"10.1007/s12035-025-05074-2","DOIUrl":"https://doi.org/10.1007/s12035-025-05074-2","url":null,"abstract":"<p><p>Primary open-angle glaucoma is the most common form of glaucoma worldwide and one of the leading causes of irreversible blindness. Current therapies focus on intraocular pressure control despite substantial evidence on the importance of additional pathogenic mechanisms involved in neuronal repair and regeneration. Some of these mechanisms may be shared with and across other neurodegenerative disorders, such as Alzheimer's disease. Joint analyses that address this pathogenic overlap can be leveraged to identify suspected neurodegenerative and neuroprotective pathways. In this study, we derived gene-level summary statistics from available genome-wide association studies for primary open-angle glaucoma and Alzheimer's Disease and employed a multivariate analysis to identify genes with an effect on both neurodegenerative diseases. We assessed the influence of the prioritized genes using Mendelian randomization to obtain the effect of retina- and brain cortex-specific gene expression on primary open-angle glaucoma risk. We identified ten genes with evidence of a pleiotropic effect on primary open-angle glaucoma and Alzheimer's disease: TMCO1, ANXA11, ARHGAP27, PLEKHM1, CRHR1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1. Additionally, gene expression in either the retina or brain cortex of TMCO1, ANXA11, ARHGAP27, PLEKHM1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1 influenced POAG risk. These genes have known roles in neurodegeneration-associated pathways. Our analysis uncovered evidence of pleiotropy and gene expression as a mechanism impacting disease risk. Further investigation into these genes may yield valuable insights into their involvement in neurodegenerative pathways potentially informing new approaches for early detection, classification, and treatment strategies.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136326","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":"Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.","authors":"Swati Jain, Debanjana Das, Abhiyanta Mukherjee, Ipsita Roy","doi":"10.1007/s12035-025-05075-1","DOIUrl":"https://doi.org/10.1007/s12035-025-05075-1","url":null,"abstract":"<p><p>Hexanucleotide (GGGGCC) repeat expansion in non-coding region of C9ORF72 is the main genetic cause of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Gain of toxic function, via RNA or proteins, or loss of function via haploinsufficiency, are probable mechanisms of disease progression. Expanded GGGGCC repeat codes for dipeptide repeat (DPR) proteins which form inclusions in the brain. Among all the dipeptides, aggregates formed by polyGA sequence are the most toxic. In this work, inhibition of aggregation of polyGA DPRs using aptamers has been explored as a therapeutic strategy to delay disease progression. Target-specific, high-affinity RNA aptamers were selected against monomeric (GA)₃₀. Selected aptamers showed significant inhibition of aggregation of (GA)₃₀ in vitro. Inhibitory RNA sequences were seen to form typical secondary structures which was missing in a non-inhibitory sequence. Some of the RNA aptamers showed increased solubilisation of DPRs formed by (GA)₃₀ and (GA)₆₀ in a neuronal cell model of ALS-FTD. Decreased aggregation was accompanied by lower oxidative stress and improved cell survival. Importantly, expression level of one of the markers of autophagy was significantly enhanced in the presence of aptamers, explaining lower aggregation observed in these cells. Thus, aptamers may be developed as potential therapeutic agents in C9 ALS-FTD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136265","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 Neuronal Exosome Cargo as Biomarkers of Neuroplasticity in Cushing's Syndrome.","authors":"Marica Pagliarini, Loretta Guidi, Caterina Ciacci, Roberta Saltarelli, Monia Orciani, Marianna Martino, Maria Cristina Albertini, Giorgio Arnaldi, Patrizia Ambrogini","doi":"10.1007/s12035-025-05069-z","DOIUrl":"https://doi.org/10.1007/s12035-025-05069-z","url":null,"abstract":"<p><p>The hippocampus is the main target of glucocorticoids (GCs) in the brain since it contains the greatest concentration of the specific receptors. GCs are among the factors modulating adult hippocampal neurogenesis (AHN), which occurs in mammalians, including humans. Prolonged exposure to high GC levels triggers AHN impairment and induces affective and cognitive deficits, consistently with hippocampal neurogenesis functions. Cushing's syndrome (CS) is a rare endocrine disorder characterized by persistently elevated GC levels, namely, cortisol, that also results in affective disorders and impairment of hippocampus-associated memory, suggesting a disruption of hippocampal neurogenesis. Players of adult neurogenesis process, such as Neural Stem/Progenitor Cells and differentiating neuronal cells, release exosomes able to cross brain blood barrier, reaching the peripheral blood. MicroRNAs are known to be selectively enriched in neuronal exosomes and to play a crucial role in adult neurogenesis regulation. The main question addressed in this exploratory study was whether neuroplasticity-related microRNAs (miRNAs), carried by neuronal-derived exosomes in peripheral blood, could reflect alterations in neurogenic processes associated with Cushing's syndrome. Hence, in the present work, we measured the content in selected miRNAs of neuronally derived exosomes in peripheral blood of patients affected by endogenous and active CS and age and sex-matched healthy subjects. The human miRNAs (miR-126, miR-9, miR-223, miR-34a, miR-124a, and miR-146a) were quantified by RT-qPCR. All the miRNAs analyzed were significantly differentially expressed in CS patients as compared to healthy subjects. Our findings support the following: (i) patients with Cushing's syndrome (CS) may exhibit a putative dysregulation of neurogenesis that could underlie the early-onset impairment of affective and cognitive functions; (ii) the exosomal cargo may represent a potential biomarker for monitoring functional and dysfunctional neuroplasticity processes in adult humans. Additional studies are needed to confirm and expand upon the findings across a wider cohort of patients.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143077","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":"Peripheral Choroid/RPE/Sclera as a Shared Pathogenic Hub: Multi-Tissue Transcriptomic Profiling Identifies Common Differentially Expressed Genes in Age-Related Macular Degeneration and Alzheimer's Disease.","authors":"Manjuan Peng, Qi Zeng, Wei Zheng, Xiaobo Xia","doi":"10.1007/s12035-025-05078-y","DOIUrl":"https://doi.org/10.1007/s12035-025-05078-y","url":null,"abstract":"<p><strong>Background: </strong>Age-related macular degeneration (AMD) and Alzheimer's disease (AD), two prevalent neurodegenerative disorders, share overlapping pathophysiological features yet lack cross-disease therapeutic strategies. This study systematically investigates their parallel genes and shared molecular mechanisms to identify potential therapeutic targets for dry AMD, a condition with limited treatment options.</p><p><strong>Methods: </strong>Transcriptomic datasets for AMD (GSE155154) and AD (GSE95587) were retrieved from the GEO database. AMD tissues were stratified into four subgroups: macular retina (MR), macular choroid/RPE/sclera (MCRS), peripheral retina (PR), and peripheral choroid/RPE/sclera (PCRS). Common differentially expressed genes (DEGs) were identified and analyzed via functional enrichment (GO, KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks. Drug-gene interactions and competing endogenous RNA (ceRNA) networks were constructed to prioritize therapeutic targets. Key hub genes were experimentally validated in a sodium iodate-induced AMD murine model using RT-qPCR.</p><p><strong>Results: </strong>Comparative analysis revealed 89, 56, 4, and 130 common DEGs between AD and MR, MCRS, PR, and PCRS subgroups, respectively. Neuroactive ligand-receptor interactions were prioritized in MR/MCRS-AD analyses, while extracellular matrix organization emerged as the dominant pathway in PCRS-AD comparisons. GSEA identified conserved the TNFα signaling pathway via NF-κB across both diseases. PCRS exhibited consistent expression trends for shared genes and pathways with AD. Computational screening prioritized seven druggable targets (COL1A1, COL1A2, COL3A1, MMP2, MMP9, VCAN, ITGA5) with dual therapeutic potential, along with a reconstructed circRNA (circRNA_002179)-miRNA (miR-124)-mRNA (VCAN) regulatory axis. Experimental validation in a sodium iodate-induced AMD murine model confirmed region-specific dysregulation: hub genes were significantly downregulated in MCRS but upregulated in PCRS.</p><p><strong>Conclusions: </strong>Our study delineates both convergent and divergent molecular landscapes of AMD and AD, with PCRS emerging as a critical locus for shared pathophysiology. These findings bridge a critical gap in understanding AMD-AD comorbidity, offering actionable strategies for targeted drug development.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136328","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":"Investigating the Role of Neutrophil Extracellular Traps as a Therapeutic Target in Traumatic Brain Injury: a Systematic Review and Meta-analysis.","authors":"Elliott Slough, Anna Pitt-Francis, Antonio Belli, Zubair Ahmed, Valentina Di Pietro, Andrew R Stevens","doi":"10.1007/s12035-025-05053-7","DOIUrl":"https://doi.org/10.1007/s12035-025-05053-7","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with few treatment options to mitigate secondary injury. Neutrophil extracellular traps (NETs) may present a potential target for therapy. The systematic review objectives were to characterise NET formation as a feature following TBI; assess the effect of NET modulatory strategies on outcomes; and investigate the relative efficacy of NET modulatory methods. A systematic review was performed, with inclusion criteria of pre-clinical or clinical studies using any model or severity of TBI, and any investigation of the pathophysiological role of NETs and/or modulation of NETs for therapeutic benefit. Following search completion, 849 records were identified with 13 studies eligible for inclusion. All 13 studies characterised NET formation in blood and brain tissue from pre-clinical TBI models, whilst four studies also demonstrated NET formation in serum and brain tissue of TBI patients. Meta-analysis (where ≥ 3 studies reported outcomes) identified that NET modulation was associated with significant improvement of outcomes in preclinical studies, in both modified neurological severity score and latency to falls. No difference in efficacy was identified between NET modulatory methods after sub-group analysis. In addition, the overall risk of bias was judged as high in the included studies. This systematic review and meta-analysis demonstrated that NETs present a promising TBI therapeutic target for future clinical validation. However, the high bias limits this systematic review, and further high-quality studies are required to make definitive conclusions about NET utility as a viable therapeutic strategy in TBI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128055","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":"Aberrant Expression of TH2LCRR and GATA3 in Peripheral Blood Mononuclear Cells of Patients with Acute-Phase Schizophrenia: Integrative Bioinformatics Analysis and Experimental Study.","authors":"Elahe Moghiseh, Ali Massoudifar, Nahid Davoodian, Pegah Mousavi, Soudeh Afsharpour, Masoumeh Mahmoodi","doi":"10.1007/s12035-025-05060-8","DOIUrl":"https://doi.org/10.1007/s12035-025-05060-8","url":null,"abstract":"<p><p>Although evidence suggests that an imbalance in Th1 and Th2 cell responses contributes to the pathogenesis of schizophrenia, the epigenetic mechanisms involved remain largely unknown. Here, we applied a combination of bioinformatics and experimental approaches to evaluate the alterations in Th1 and Th2-related genes in schizophrenia patients. Based on bioinformatics analysis, we selected Th1 (IFNG-AS1, TBX21, IFNG) and Th2-related genes (TH2LCRR, GATA3, IL-4), which are potentially implicated in the pathogenesis of schizophrenia. For experimental validation, we measured the expression levels of these transcripts in peripheral blood mononuclear cells (PBMCs) from patients with acute-phase schizophrenia and controls. Bioinformatics findings revealed 2 lncRNAs, 9 miRNAs, 76 mRNAs, and 234 transcription factors (TFs) related to Th1 and Th2 cell lineages, which are involved in schizophrenia. Subsequent analysis of qPCR data showed a remarkable increase in the expression levels of GATA3 and TH2LCRR in the PBMCs of patients with schizophrenia compared to controls. Interestingly, both TH2LCRR and GATA3 exhibited greater diagnostic value in female subjects. However, our data showed no significant difference in the expression levels of Th1-related genes (IFNG-AS1, TBX21, IFNG) and IL-4 between diagnostic groups. Furthermore, the expression levels of IFNG-AS1 and TH2LCRR were positively correlated with cytokine expression in patient subjects. These findings further support the pivotal role of Th1/Th2 imbalance in the pathogenesis of schizophrenia. Our data highlight the necessity to evaluate the potential efficacy of immune-related genes to identify promising biomarkers for both the diagnosis and therapy of patients with schizophrenia.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128047","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":"The Intricate Relationship of Trk Receptors in Brain Diseases and Disorders.","authors":"Sarthak Dahiya, Poonam Sharma, Bhupesh Sharma, Priyanka Saroj, Harsha Kharkwal, Nitin Sharma","doi":"10.1007/s12035-025-05058-2","DOIUrl":"https://doi.org/10.1007/s12035-025-05058-2","url":null,"abstract":"<p><p>The tropomyosin-related tyrosine kinases or neurotrophic tyrosine kinase receptors are a group of tyrosine kinases that play a crucial role in regulating neuronal growth and development. Neurotrophins are a class of protein-secreting cells that serve as the primary ligand for the Trk receptors. The four primary neurotrophins are nerve growth factor (NGF), brain-derived nerve factor (BDNF), neurotrophin-3, and neurotrophin-4/5. Mounting evidence suggests that Trk receptors can be categorized into three types: TrkA, TrkB, and TrkC. These receptors play a crucial role in facilitating neuronal growth and development. Trk receptors influence the survival and differentiation of neurons via many signalling cascades. Neurotrophin interaction with Trk receptors triggers a signalling cascade involving PLC, PI3K/Akt, and Ras/MAPK signalling pathways. Emerging evidence suggests that diminished neurotrophic support, changes in Trk receptor expression, or disruptions in signalling cascades play a crucial role in the development of various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), autism spectrum disorder (ASD), and many more. This review specifically explores therapeutic approaches targeting Trk receptors, their ligands, and Trk signaling in the context of various brain disorders. We focus on the potential for modulating or inhibiting Trk receptors as a treatment strategy for brain diseases.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128016","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}