CNS Neuroscience & Therapeutics最新文献

{"title":"Fatty Acid-Binding Protein 5 Potentially Regulates the Proliferation and Metastasis of Uveal Melanoma Cells Through the PI3K/AKT/mTOR Signaling Pathway.","authors":"Yue Du, Xue Jiang, Yanyan Zhang, Jianing Ying, Quanyong Yi","doi":"10.1002/cns.71112","DOIUrl":"10.1002/cns.71112","url":null,"abstract":"<p><strong>Background: </strong>Uveal melanoma (UVM) is an aggressive intraocular tumor with limited effective treatments for metastatic disease. This study explored the pathways through which fatty acid-binding protein 5 (FABP5) promoted UVM progression.</p><p><strong>Methods: </strong>Single-cell RNA sequencing datasets were preprocessed by the Seurat package, and prognostic genes were screened using the survival package. A prognostic model was constructed via LASSO Cox regression, followed by Kaplan-Meier (KM) survival analysis. To characterize the tumor immune microenvironment, we evaluated immune cell infiltration using ssGSEA, ESTIMATE, and CIBERSORT algorithms, while GSEA was applied to identify enriched pathways. Additionally, immunotherapy response was predicted by TIDE, and tumor mutation burden (TMB) was calculated using Maftools. For in vivo validation, a nude mouse xenograft model was established, and Western blotting was performed on tumor tissues harvested from the xenograft assay.</p><p><strong>Results: </strong>SPON2, MATK, and FABP5 were identified as hub genes in UVM and used to construct a prognostic model with a high AUC. Immune infiltration analysis revealed that high-risk patients exhibited features of immune evasion. Enrichment analysis further revealed that cytotoxic T-cell-related genes (MATK and FABP5) were enriched in the PI3K/AKT/mTOR pathway. FABP5 was overexpressed in UVM cells, whereas FABP5 silencing suppressed cell viability, proliferation, migration, and invasion, reduced MMP2 and MMP9 levels, promoted apoptosis, downregulated PI3K/AKT/mTOR pathway-related molecules, and upregulated apoptosis-related proteins. Notably, these effects could be reversed by the PI3K agonist 740Y-P.</p><p><strong>Conclusion: </strong>FABP5 promoted UVM cell proliferation and migration through the PI3K/AKT/mTOR pathway. Though the immune-infiltration analysis was hypothesis-generating, it may help identify patients likely to benefit from immunotherapy.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71112"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13542988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep Deprivation Induces Glial Dysfunction, Synaptic Loss, Metabolic Imbalance, and Cognitive Impairment in 12-Month-Old Mice: Protective Effects of D30.","authors":"Xueyan Liu, Huiling Lin, Jian Zhong, Xili Chen, Zonglin Wang, Meng Shi, Hang Shi, Hui Zhang, Ping Chen, Zu-Cheng Ye","doi":"10.1002/cns.71134","DOIUrl":"10.1002/cns.71134","url":null,"abstract":"<p><strong>Background: </strong>Sleep deprivation (SD) has been increasingly implicated in age-related cognitive decline. However, the mechanisms linking SD duration to progressive disruption of glial homeostasis, synaptic vulnerability, and metabolic dysregulation remain poorly defined.</p><p><strong>Methods: </strong>We employed 12-month-old Thy1-EGFP and Cx3CR1-EGFP mice to investigate the effects of short-term sleep deprivation (SSD) and long-term sleep deprivation (LSD) on neuronal architecture, microglial morphology, and astrocytic homeostasis. Quantitative analyses included dendritic spine density, synaptic protein expression, glial morphological and transcriptional markers, and untargeted plasma metabolomics. The neuroprotective effects of D30, a novel small molecule compound, were also evaluated.</p><p><strong>Results: </strong>SSD induced relatively transient oxidative stress and glial suppression, whereas LSD led to sustained reductions in dendritic spine density, synaptic protein levels, and microglial/astrocytic morphological complexity. LSD further disrupted mitochondrial metabolism, notably involving the TCA cycle, AMPK-associated signaling, and lipid homeostasis. Treatment with D30 significantly ameliorated LSD-induced deficits by preserving glial homeostatic features, restoring synaptic protein expression, maintaining dendritic spine density, and rebalancing systemic metabolism, ultimately improving cognitive performance.</p><p><strong>Conclusions: </strong>LSD impairs glial homeostatic integrity and synaptic stability in association with systemic metabolic dysfunction in middle-aged mice. D30 effectively alleviates these impairments, highlighting its potential as a protective intervention for chronic SD-related neurocognitive dysfunction.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71134"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the Distinctive Brain Functional Dynamics Between Parkinson's Disease and Progressive Supranuclear Palsy.","authors":"Chenfei Ye, Jiahui Shi, Jiliang Fang, Tao Wu, Piu Chan, Jinghong Ma, Ting Ma","doi":"10.1002/cns.71147","DOIUrl":"10.1002/cns.71147","url":null,"abstract":"<p><strong>Background: </strong>Dynamic analysis of resting-state fMRI (rs-fMRI) offers a novel approach to differentiate Parkinson's disease (PD) from progressive supranuclear palsy (PSP) by capturing temporal features of brain network activity, which may shed light on the mechanisms underlying non-motor symptoms.</p><p><strong>Objectives: </strong>To characterize differences in brain dynamics between PD and PSP using dynamic brain metrics, evaluate their exploratory discriminative performance, and investigate associations with non-motor symptoms.</p><p><strong>Methods: </strong>Sixty-nine healthy controls, 82 PD patients, and 29 PSP patients underwent standardized clinical assessment and rs-fMRI. Hidden Markov models extracted temporal features including fraction occurrence (FO), dwell time, and transition probability. These metrics were used for group comparisons, correlation analyses, and machine learning classification.</p><p><strong>Results: </strong>PD and PSP showed opposite trends in fraction occurrence of unimodal network-dominant states. Compared to PD and controls, PSP exhibited prolonged duration in the dorsal attention and limbic network (DAN&LIM) state and increased occurrence in the dorsal attention and frontoparietal control network (DAN&FPCN) state. Reduced unimodal state occupancy correlated with cognitive decline in both groups, while increased DAN&LIM and unimodal persistence linked to worse mood and sleep disturbances in PSP. Machine learning with these metrics achieved moderate accuracy in differentiating PD from PSP.</p><p><strong>Conclusions: </strong>Temporal features of brain network dynamics may provide candidate imaging markers for distinguishing PD and PSP while offering mechanistic insights into non-motor symptomatology. However, their diagnostic applicability requires validation in independent external multicenter cohorts.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71147"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical Age-Related Patterns of Neural Signal Complexity in Autism Spectrum Disorder.","authors":"Junxia Han, Linya Liang, Rihong Song, Xiaozhou Zhang, Jiayu Liu, Guoqian Jiang, Xiaoli Li","doi":"10.1002/cns.71173","DOIUrl":"10.1002/cns.71173","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is increasingly conceptualized as a neurodevelopmental condition involving atypical organization of large-scale neural dynamics. While EEG studies have largely focused on spectral power and connectivity, how neural signal complexity is organized across development in ASD remains poorly understood.</p><p><strong>Methods: </strong>Resting-state EEG was recorded from 186 children aged 3-11 years, including children with ASD and typically developing (TD) peers. Participants were further categorized into preschool-aged and school-aged groups to examine developmental differences. Multiscale entropy (MSE) was computed across 20 temporal scales to characterize neural signal complexity, and group differences, age-related patterns, and associations with autism symptom severity were examined.</p><p><strong>Results: </strong>Across the full sample, children with ASD exhibited significantly higher MSE than TD children across brain regions and temporal scales. Group differences were most pronounced in preschool-aged children, whereas in school-aged children they were more restricted to lower temporal scales and frontoparietal regions. In TD children, MSE increased robustly with age across scales, while age-related associations in ASD were more variable and region-specific. Additionally, individual differences in MSE were associated with autism symptom severity, particularly in frontal and parietal regions.</p><p><strong>Conclusion: </strong>These findings indicate that ASD is characterized by atypical developmental organization of neural signal complexity across temporal scales, underscoring the importance of a multiscale developmental perspective for understanding neural dynamics in autism.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71173"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.","authors":"Kang Pan, Keyi Zhu, Yajun E, Yucang He, Siqi Ding","doi":"10.1002/cns.71167","DOIUrl":"10.1002/cns.71167","url":null,"abstract":"<p><strong>Background: </strong>Epilepsy is a heterogeneous central nervous system disorder characterized by recurrent seizures and is frequently accompanied by cognitive and neuropsychiatric comorbidities. Although apolipoprotein E4 (ApoE4) is well established as a genetic risk factor in Alzheimer's disease, its role as a modifier of epilepsy susceptibility, progression, and therapeutic response remains incompletely understood.</p><p><strong>Objective: </strong>This review aims to summarize current evidence regarding the molecular mechanisms, clinical implications, and therapeutic potential of ApoE4 in epilepsy, with emphasis on its relevance to precision medicine.</p><p><strong>Methods: </strong>A narrative review was conducted by synthesizing preclinical and clinical studies investigating the relationship between ApoE4 and epilepsy, including mechanisms related to neuroinflammation, synaptic dysfunction, lipid metabolism, blood-brain barrier (BBB) integrity, clinical phenotypes, and targeted therapeutic strategies.</p><p><strong>Results: </strong>ApoE4 contributes to epileptogenesis through multiple interconnected pathways. It promotes neuroinflammatory responses by activating microglia and inflammatory signaling, disrupts synaptic plasticity through N-methyl-D-aspartate receptor dysfunction and excitation-inhibition imbalance, impairs lipid and energy metabolism leading to neuronal hyperexcitability, and compromises BBB integrity. Clinically, ApoE4 carriers show increased seizure susceptibility, accelerated cognitive decline, hippocampal atrophy, and variable responsiveness to antiseizure medications. Emerging therapeutic approaches include ApoE4 structural correction, modulation of metabolic and inflammatory pathways, and gene-based interventions.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71167"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NG2-Glia in Central Nervous System Following Injury: From Pathological Involvement to Repair Potential.","authors":"Yunyun Cai, Xin Shen, Ming Li, Junjie Li, Gang Chen","doi":"10.1002/cns.71162","DOIUrl":"10.1002/cns.71162","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Central nervous system (CNS) injury remains a severe neurological condition with limited regenerative capacity. NG2-glia are abundant and functionally versatile glial cells that have attracted increasing attention in CNS repair research. However, their roles are complex and context-dependent, ranging from early pathological involvement to later reparative potential, and a systematic synthesis of this temporal dichotomy is lacking.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Method: &lt;/strong&gt;We systematically searched PubMed and Web of Science from inception to 2026 using combinations of keywords including \"NG2-glia,\" \"NG2 cells,\" \"oligodendrocyte precursor cells,\" \"OPCs,\" and \"CNS injury.\" Additional references were identified by manual screening of reference lists. We prioritized mechanistic and therapeutic studies published within the last 10 years, while foundational discoveries were included for historical context.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;This review establishes that NG2-glia exhibit a time-dependent dual role after CNS injury. In the early stage (hours to days), they rapidly proliferate, migrate to the lesion, and secrete chondroitin sulfate proteoglycans (CSPGs), forming a chemical and physical barrier that inhibits axonal regeneration and may facilitate neuropathic pain. In the middle-to-late stages (days to weeks/months), they shift toward repair functions, including remyelination via differentiation into oligodendrocytes, neuronal trans-differentiation (primarily under forced reprogramming), and anti-inflammatory/neuroprotective effects through interactions with microglia, astrocytes, and neurons. Their fate is determined by intrinsic factors (age, heterogeneity) and extrinsic microenvironmental signals (damage-associated molecules, cytokines, and signaling pathways such as Wnt/β-catenin and TGF-β2). Therapeutically, diverse strategies-including CB1 receptor agonists to promote remyelination, chondroitinase ABC to neutralize CSPG inhibition, and SOX2/NeuroD1-based reprogramming to generate functional neurons-have shown preclinical promise, yet significant translational gaps remain, including poor endogenous neurogenesis, constitutive differentiation limitations, and safety concerns.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion and perspective: &lt;/strong&gt;Targeting NG2-glia offers a novel avenue for CNS repair, but successful interventions must be precisely timed and stage-specific rather than unregulated promotion or inhibition. This review proposes an analytical framework of \"time-dependent dual roles\" to reconcile the contradictory functions of NG2-glia and highlights critical future directions, including deciphering regional heterogeneity, elucidating the molecular switches that govern state transitions, validating the functional integration of reprogrammed neurons, and bridging the bench-to-bedside divide. A deeper understanding of the regulatory logic underlying NG2-glia plasticity will inform next-generation precision therapies for CNS injurie","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71162"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148965790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deltex 2 Mediates Oxidative Stress and Neurotoxicity in Freezing of Gait of Parkinson's Disease via the Notch2-Nrf2 Axis.","authors":"Qibin Zheng, Xiaohua Zheng, Junxin Zhao, Lin Lin, Yibiao Chen, Huiqing Wang, Zhangya Lin, Lianghong Yu","doi":"10.1002/cns.71135","DOIUrl":"10.1002/cns.71135","url":null,"abstract":"<p><strong>Background: </strong>Freezing of gait (FOG) is a disabling symptom of advanced Parkinson's disease (PD) with limited therapeutic options. This study identifies Deltex 2 (DTX2) as a novel molecular driver of FOG and elucidates its mechanism.</p><p><strong>Methods: </strong>FOG rat models were established by bilateral injections of 6-hydroxydopamine (6-OHDA) into the dorsal striatum and bilateral infusions of immunotoxin 192 IgG-saporin into the basal forebrain regions. Proteomic sequencing was performed to identify differentially expressed proteins in the striatum. In vitro studies employed human dopaminergic-like SH-SY5Y cells differentiated with retinoic acid. Cellular responses were evaluated by assessing cell viability, apoptosis, reactive oxygen species (ROS) levels, dopamine content, and tyrosine hydroxylase (TH) expression.</p><p><strong>Results: </strong>Proteomic profiling revealed significantly elevated DTX2 levels in the striatum of FOG model rats. In vitro, DTX2 knockdown in differentiated SH-SY5Y cells conferred robust protection against 6-OHDA-induced neurotoxicity and oxidative stress, as evidenced by increased cell viability, reduced apoptosis, and diminished ROS accumulation. DTX2 silencing restored dopamine synthesis and TH expression. Mechanistically, DTX2 promoted oxidative stress by ubiquitinating and degrading Notch2, a positive regulator of Nrf2 transcriptional activity. Conversely, DTX2 interference stabilized Notch2, thereby enhancing Nrf2 signaling and antioxidant defense. In vivo, striatal knockdown of DTX2 in FOG rats markedly ameliorated gait abnormalities and improved survival of dopaminergic neurons.</p><p><strong>Conclusion: </strong>DTX2 emerges as a key molecular driver of freezing of gait in PD. Pharmacological or genetic suppression of DTX2 stabilizes the Notch2-Nrf2 antioxidant axis, rescuing neurons and restoring motor performance in rodent models. These findings identify DTX2 as a readily druggable target for precision therapy aimed at alleviating FOG and improving mobility in patients with advanced PD.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71135"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149000985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mild Cognitive Impairment Diagnosis and Care Algorithms and the Role of Digital Interventions: Expert Consensus.","authors":"Nagaendran Kandiah, Yee Fai Chan, Darwin Dasig, Jacqueline Dominguez, Kar Chai Koh, Si Ching Lim, Paulus Anam Ong, Encarnita Raya-Ampil, Raymond Chee Seong Seet, Vorapun Senanarong, Kit Mun Tan, Maw Pin Tan, Trần Công Thắng, Tong Mai Trang, Yuda Turana, Cuibai Wei, Ralf Ihl","doi":"10.1002/cns.71085","DOIUrl":"10.1002/cns.71085","url":null,"abstract":"<p><strong>Background: </strong>Mild cognitive impairment (MCI) is a clinically recognized condition, often being a prodromal dementia state with a risk of further cognitive decline. While there is currently no definitive diagnostic test for MCI, early identification and intervention are important.</p><p><strong>Methods: </strong>To assist clinicians in the diagnosis and treatment of MCI, the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) convened to identify ongoing gaps in MCI management primarily in Asia, and to discuss the existing body of literature with a view to providing evidence-based expert recommendations.</p><p><strong>Results: </strong>Two novel algorithms and a set of expert recommendations were formulated, addressing the cognitive assessment and clinical diagnosis of MCI, and optimal MCI management approaches. Because many risk factors for cognitive decline are modifiable, the mainstay of intervention comprises a multi-domain approach involving optimizing metabolic health, mitigating cerebrovascular risk, correcting hearing and vision loss, treating depression, encouraging engagement in cognitive exercises and social connection, and avoiding harmful substances. Digital interventions are becoming increasingly important as tools for cognitive assessment, as well as for cognitive stimulation and to help patients self-manage and maintain their independence. Pharmacologic approaches for MCI management include medical management of cardiovascular risk, reducing cholinergic burden and the use of drugs known to sedate or affect cognitive function, and evidence-based medications that have demonstrated benefit specifically in MCI.</p><p><strong>Conclusions: </strong>These evidence-based recommendations are intended to support clinicians, particularly in primary care, to identify MCI and plan an intervention strategy to help slow age-related cognitive decline.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71085"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of METTL14 Alleviates OGD/R-Induced Neuronal Differentiation Injury in Neural Stem Cells Through Suppressing the Tp53inp2/Ptgs2 Axis: Potential Benefits for the Mouse MCAO Model.","authors":"Dan Hou, Yujie Hu, Tian Yun, Dan Yu, Guoshuai Yang","doi":"10.1002/cns.71099","DOIUrl":"10.1002/cns.71099","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke (IS) is an acute cerebrovascular disease characterized by high morbidity and mortality, with limited current treatment options. Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is known to be a positive regulator of autophagy under physiological conditions, but the mechanism of Tp53inp2 in IS remains unclear. In this study, we aimed to explore the mechanism of Tp53inp2 in IS.</p><p><strong>Methods: </strong>Primary neural stem cells (NSCs) were extracted and identified. An OGD/R cell model was constructed. Tp53inp2 was knocked down and rapamycin was added. A middle cerebral artery occlusion (MCAO) animal model was constructed, and then 5 μL of 5 × 10⁵ NSCs, either untreated or transfected with sh-NC or sh-Tp53inp2, were injected. Additionally, at the cellular level, Ptgs2 or Tp53inp2 was overexpressed, and METTL14 was knocked down.</p><p><strong>Results: </strong>Inhibition of Tp53inp2 mitigated OGD/R-induced mitophagy and ROS levels in vitro. Moreover, inhibition of Tp53inp2 mediated neuronal differentiation of OGD/R treated NSCs by suppressing mitophagy. At the animal level, the transplantation of NSCs with a knockdown of Tp53inp2 increased neuronal differentiation, thereby alleviating the effects of MCAO and mitigating cognitive impairments in MCAO model mice. Ptgs2 was further screened and validated as a downstream target mediating the effect of Tp53inp2 on NSCs. At the cellular level, Tp53inp2 alleviated OGD/R-induced mitophagy and ROS levels by regulating Ptgs2 expression. METTL14 could regulate Tp53inp2 expression by modulating the functional m6A modification sites on Tp53inp2 mRNA. Inhibition of METTL14 alleviated OGD/R-induced mitophagy and the rise of ROS levels in NSCs by inhibiting the Tp53inp2/Ptgs2 axis.</p><p><strong>Conclusions: </strong>Inhibition of METTL14 alleviated OGD/R-induced neuronal differentiation injury in NSCs by inhibiting the Tp53inp2/Ptgs2 axis. By elucidating the mechanisms involving Tp53inp2, Ptgs2, and METTL14, this research offers a foundation for developing new strategies to enhance neuronal differentiation and mitigate cognitive impairments in stroke patients.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71099"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Transdiagnostic Subtypes in Emotional Disorders.","authors":"Yun Wu, Chun Wang, Changjun Teng, Yan Lu, Chengbin Guan, Yuan Zhong","doi":"10.1002/cns.71122","DOIUrl":"10.1002/cns.71122","url":null,"abstract":"<p><strong>Background: </strong>Emotional disorders (EDs), including anxiety disorders, major depression (MDD), and post-traumatic stress disorder (PTSD), show overlapping symptoms and neurobiological heterogeneity, limiting current diagnostic frameworks. Transdiagnostic biomarkers are critical for precision psychiatry.</p><p><strong>Methods: </strong>Resting-state functional connectivity (FC) from 261 ED patients and 201 healthy controls (HCs) was decomposed via nonnegative matrix factorization (NMF). Differential FC features defined latent disease factors, classifying patients into subtypes with distinct network/structural profiles.</p><p><strong>Results: </strong>The analysis identified five representative functional networks (RFNs) underlying the heterogeneity of emotional disorders. RFN1 reflected connectivity between sensorimotor and dorsal attention networks, while RFN2 was defined by theory-of-mind-related connectivity. RFN3, characterized by thalamocortical connections, was specifically linked to somatic sensation processing. RFN4 involved connectivity within the default mode network, and RFN5 captured multi-network-subcortical integration. These RFNs delineated five subtypes with distinct clinical profiles: ST1 (mixed anxiety/depression) exhibited RFN1-driven somatic vigilance and comorbid depressive symptoms; ST2 (mild symptoms) demonstrated resilience associated with RFN2; ST3 (somatic anxiety-dominant) showed RFN3-related elevations in somatic anxiety and panic symptoms; ST4 (anxiety-centric) was marked by RFN4-associated self-referential anxiety; and ST5 represented a depression-pure subgroup mapped to RFN5.</p><p><strong>Conclusion: </strong>This study proposes a neurobiologically informed stratification for EDs, revealing transdiagnostic subtypes with distinct network signatures and clinical implications. The findings bridge symptom heterogeneity to circuit-level dysfunction, offering potential biomarkers for personalized interventions and advocating for transdiagnostic approaches in psychiatric research.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":"e71122"},"PeriodicalIF":6.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}