Neurobiology of Disease最新文献

{"title":"Cryo-EM advances in TDP-43 amyloid fibrils structure determination.","authors":"Zhengdong Xu, Xi Chen, Wenjuan Yi","doi":"10.1016/j.nbd.2026.107659","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107659","url":null,"abstract":"<p><p>TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107659"},"PeriodicalIF":6.0,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216492","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":"Neuronal progranulin in the medial prefrontal cortex mediates stress-induced despair-like behaviors and impaired neuroplasticity.","authors":"Yunfeng Wang, Yao Yang, Siman Guo, Genmin Sun, Zijin Cai, Xiyao Chen, Fang Liu, Yuan Li","doi":"10.1016/j.nbd.2026.107649","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107649","url":null,"abstract":"<p><strong>Background: </strong>Neuroplasticity in the medial prefrontal cortex (mPFC) is critically implicated in major depressive disorder (MDD). Progranulin (PGRN), a multifunctional protein that is abundant in the cortex, regulates neuronal development and synaptic maintenance, positioning it as a candidate therapeutic target for MDD. However, current findings indicate the effects of PGRN in depression are contingent upon both brain region and cell type. Whether neuronal PGRN in the mPFC contributes to the pathogenesis of depression remains unknown.</p><p><strong>Methods: </strong>A chronic unpredictable mild stress (CUMS) mouse model was established, followed by depression-related behavioral tests. PGRN expression levels were determined by western blotting and immunofluorescence. Adeno-associated virus (AAV)-mediated neuronal Grn knockdown was performed in the mPFC in vivo to assess the functional contribution of PGRN. Neuronal morphology was evaluated by Golgi staining and Sholl analysis. Transcriptional changes were profiled by RNA sequencing to explore potential mechanisms, with bioinformatics analyses including differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network analysis.</p><p><strong>Results: </strong>PGRN expression was increased in mPFC neurons after CUMS exposure. Neuronal Grn knockdown in the mPFC partially reversed CUMS-induced despair-like behaviors and impaired dendritic plasticity. Transcriptomic analysis further revealed that Grn knockdown restored CUMS-induced neuroplasticity-related transcriptional alterations, including genes involved in Ephrin signaling, planar cell polarity, and MYC-related transcriptional programs.</p><p><strong>Conclusion: </strong>These findings suggest that neuronal PGRN in the mPFC contributes to the despair-like phenotype, likely through modulation of neuroplasticity. Targeting neuronal PGRN may represent a potential strategy for developing novel antidepressant interventions.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107649"},"PeriodicalIF":6.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207524","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":"Proteinopathies and glial cells.","authors":"Sally A Frautschy, David Blum","doi":"10.1016/j.nbd.2026.107656","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107656","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107656"},"PeriodicalIF":6.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207594","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 glymphatic system as a mechanistic bridge between migraine and sleep: Evidence from clinical studies and animal models.","authors":"Byoungchul Choi, Songyi Park, Jae-Jun Lee, Jong-Hee Sohn","doi":"10.1016/j.nbd.2026.107654","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107654","url":null,"abstract":"<p><p>Migraine is a highly prevalent, disabling neurological disorder often accompanied by sleep disturbances; however, the mechanisms linking sleep disturbance to migraine susceptibility remain unclear. The glymphatic system, a sleep-modulated perivascular clearance network facilitated by astrocytic aquaporin-4 (AQP4) and functionally connected to meningeal lymphatic drainage, is a potential mechanistic link between migraine and sleep disturbances. This review synthesizes evidence from clinical neuroimaging, cerebrospinal fluid and blood biomarker studies, and preclinical animal models to evaluate glymphatic involvement in migraine. Astrocytic AQP4 polarization, perivascular patency, and meningeal lymphatic drainage directly intersect with core migraine mechanisms, including cortical spreading depression-induced perivascular closure and calcitonin gene-related peptide (CGRP)-mediated meningeal lymphatic dysfunction. Although clinical findings are heterogeneous, glymphatic-related imaging and biomarker abnormalities appear to be more evident in association with higher attack frequency, longer disease duration, and poorer sleep quality. Animal models have linked sleep disruption, cortical spreading depression, and CGRP signaling to altered glymphatic and meningeal lymphatic functions. Four complementary hypotheses-waste accumulation, bidirectional disruption loop, the meningeal lymphatic-CGRP axis, and chronification-provide an integrative framework for this relationship across multiple timescales. These findings support the integration of sleep assessment with a glymphatic-informed framework in migraine evaluation and generate testable hypotheses that sleep-directed interventions may influence glymphatic function and that anti-CGRP therapies may partly act through meningeal lymphatic mechanisms, although these clearance-related therapeutic mechanisms remain unconfirmed in patients.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107654"},"PeriodicalIF":6.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207539","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":"Corrigendum to “nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion” [Neurobiol. Dis. 54 (2013) 105–114]","authors":"Giuseppe Pignataro,&nbsp;Elga Esposito,&nbsp;Rossana Sirabella,&nbsp;Antonio Vinciguerra,&nbsp;Ornella Cuomo,&nbsp;Gianfranco Di Renzo,&nbsp;Lucio Annunziato","doi":"10.1016/j.nbd.2026.107591","DOIUrl":"10.1016/j.nbd.2026.107591","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"229 ","pages":"Article 107591"},"PeriodicalIF":6.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment-refractory autoimmune glial fibrillary acidic protein astrocytopathy: Clinical features, predictive models, therapy.","authors":"Shifeng Zhang, Huilu Li, Haiyan Yao, Ting Li, M M Wendong Lai, M M Shiyu He, M M Peihao Lin, Jie Yang, Yaqing Shu, Dayang Hui, M M Li Huang, Cong Gao, Xiaorong Liu, Youming Long","doi":"10.1016/j.nbd.2026.107653","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107653","url":null,"abstract":"<p><strong>Background and objectives: </strong>A subset of glial fibrillary acidic protein astrocytopathy experiences treatment-refractory disease course, yet the clinical and immunological features defining this subgroup remain incompletely characterized.</p><p><strong>Methods: </strong>Patients were classified as treatment-refractory (n = 23) or treatment-responsive (n = 30). Clinical, imaging, and outcomes were compared. For subgroup analyses, refractory patients were divided into three groups: no immunoadsorption/plasma exchange (IA/PE) (n = 9), IA/PE monotherapy (n = 4), and IA/PE plus rituximab (n = 10), with functional outcomes compared across groups. Immunoglobulin G (IgG) from refractory patients was applied to a passive transfer mouse model, and single-cell RNA sequencing was performed to explore underlying pathogenic mechanisms.</p><p><strong>Results: </strong>The treatment-refractory group had higher proportion of the meningoencephalomyelitis phenotype (82.6% vs. 53.3%, P = 0.026) and more frequent disturbances of consciousness (65.2% vs. 30.0%, P = 0.011), paraplegia (78.3% vs. 33.3%, P = 0.001), and peripheral nervous system involvement (89.5% vs. 22.2%, P < 0.001). Refractory patients had elevated cerebrospinal fluid glial fibrillary acidic protein and neurofilament light chain levels. Refractory patients more frequently exhibited spinal cord lesions involving three or more segments (65.2% vs. 21.4%, P = 0.002). Disability at last follow-up was greater in the refractory group (median modified Rankin Scale score 3 vs. 1, P < 0.0001). Firth penalized regression model identified peripheral nervous system involvement as the independent predictor of treatment refractoriness (odds ratio = 10.74, P = 0.006). Among refractory patients, the IA/PE-plus-rituximab group had significantly lower long-term mRS scores than the no-IA/PE group (adjusted P = 0.031). GFAPA-IgG from refractory patients induced CD45⁺ cell infiltration in mouse brain. Single cell analysis demonstrated activation of complement and inflammatory pathways, with astrocytes adopting a pro inflammatory state.</p><p><strong>Conclusion: </strong>Treatment refractory disease is marked by severe central and peripheral nervous system injury. Convergent clinical and experimental evidence provides a rationale for B cell targeted therapies.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107653"},"PeriodicalIF":6.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183612","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":"D2 dopamine and CB2 cannabinoid receptor cooperation restores striatal LTP in an epilepsy model.","authors":"Miriam Sciaccaluga, Laura Bellingacci, Valentina Imperatore, Anna Aurora Taddei, Alessandro Tozzi, Massimiliano Di Filippo, Marta Barzasi, Fabrizio Gardoni, Marina P Sánchez, José M Serratosa, Lucilla Parnetti, Andrea Mancini, Cinzia Costa","doi":"10.1016/j.nbd.2026.107648","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107648","url":null,"abstract":"<p><p>Increasing evidence suggests that subcortical structures contribute to seizure susceptibility and cognitive impairment in several epileptic syndromes. However, research into mechanisms linking neuronal excitability and synaptic dysfunction in epilepsy has mainly focused on the cortex and hippocampus, leaving basal ganglia contributions largely unexplored. Using a genetic murine model of Lafora disease (LD), a drug-resistant form of neurodegenerative epilepsy, we performed ex vivo patch-clamp recordings to assess neuronal excitability, synaptic transmission, and plasticity of striatal medium spiny neurons. Our results reveal progressive alterations in corticostriatal transmission and long-term synaptic plasticity, including long-term potentiation (LTP). Electrophysiological and biochemical assessments showed a reduced NMDA/AMPA ratio and reduced expression of NMDA receptor subunits and dopamine receptors in striatal neurons of LD mice. Exposure to a dopamine D2 receptor agonist and to cannabidiol restored long-term plasticity in LD mice, suggesting a D2R- and CB2R-dependent synergic action on striatal LTP. Our findings highlight basal ganglia dysfunction in experimental epilepsy and suggest an unconventional dopaminergic-endocannabinoid interplay.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107648"},"PeriodicalIF":6.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183594","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":"KIF1A c.773C > T impairs neural progenitor differentiation and axonal transport in association with dysregulated Wnt/β-catenin-BDNF signaling.","authors":"Yong Liu, Jiayuan Wang, Ruonan Duan, Xiaoyi Wang, Jie Zhang, Mengru Li, Jian Sun, Yulin Zeng, Haopeng Kan, Tonghui Meng, Xinrui Liu, Yu Zhang, Jiexin Tang, Kexin Shi, Ziyu Wei, Yecheng Jin, Jiangxia Li, Xi Li, Qiji Liu, Jinlong Ma, Yuan Gao, Wenjie Sun","doi":"10.1016/j.nbd.2026.107645","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107645","url":null,"abstract":"<p><p>Pathogenic KIF1A variants are established cause neurodevelopmental and neurodegenerative disorders. However, the mechanisms by which they perturb early human neural development remains undefined. Here, we identified a heterozygous KIF1A c.773C > T (p.T258M) mutation in a Chinese family with hereditary spastic paraplegia and modeled its pathogenicity using patient-derived iPSCs and CRISPR-Cas9-corrected isogenic controls. We found that KIF1A-mutant neural stem cells (NSCs) exhibited hyperproliferation, impaired cell-cycle exit, and defective neuronal differentiation, accompanied by defective neurite outgrowth, neuronal complexity, and calcium activity. Mechanistically, the KIF1A c.773C > T mutation compromised the binding affinity of KIF1A for β-tubulin and thereby impaired microtubule-associated localization of BDNF and synaptophysin. Integrated transcriptomic and biochemical analyses further revealed dysregulation of the Wnt/β-catenin signaling pathway. Notably, pharmacological activation of Wnt signaling restored BDNF expression, whereas exogenous BDNF rescued the proliferative and differentiative defects, indicating a potential functional relationship between BDNF and Wnt/β-catenin signaling. Collectively, these findings suggested that dysregulated Wnt/β-catenin-BDNF signaling may serve as a contributory mechanism linking KIF1A motor dysfunction to aberrant neural stem cell fate.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107645"},"PeriodicalIF":6.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170013","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":"Erratum to \"The PINK1-VCP-p47 pathway protects against tau-induced dendritic shrinkage in cortical neurons through interaction with STIP1\" [Neurobiol. Dis. 229 (2026) 107592].","authors":"Sukanya Banerjee, Kent Z Q Wang, Michael R DeChellis-Marks, Madeleine R Ross, Nadine H Oury, Charleen T Chu","doi":"10.1016/j.nbd.2026.107616","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107616","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107616"},"PeriodicalIF":6.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112642","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":"Corrigendum to \"Activation of ABCC1 transporter ameliorates synaptic dysregulation in Tay-Sachs disease neuron\" [Neurobiol. Dis. 216 (2025) 107099].","authors":"Yumeng Zhang, Tadahiro Numakawa, Ryutaro Kajihara, Kiseok Lee, Jing Pu, Chisato Horita, Jun Kido, Muneaki Matsuo, Takumi Era","doi":"10.1016/j.nbd.2026.107633","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107633","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107633"},"PeriodicalIF":6.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112706","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}