Acta Neuropathologica Communications最新文献

{"title":"Immune niches in brain tumors: glial-immune cell interactions and spatial microdomains.","authors":"Qian Guo, Sihang Shen, Zhouyuan Zhang, Meirong Shan, Bochen Pan, Xiao Yu, Yi Chen","doi":"10.1186/s40478-026-02373-0","DOIUrl":"https://doi.org/10.1186/s40478-026-02373-0","url":null,"abstract":"<p><p>The immune microenvironment of brain tumors is characterized by remarkable diversity, where immune cells are not randomly distributed but are systematically organized into specific spatial microdomains. This spatial order is primarily orchestrated by glial cells, including astrocytes, microglia, and oligodendrocyte-lineage cells, which actively shape the local immune landscape by determining the position and activation states of infiltrating immune populations. To reflect the latest conceptual advances, this review first details the complex interaction networks through which glial cells directly modulate T-cell function and shape myeloid cell properties via cytokine signaling and metabolic regulation. We then examine how these active cellular communications synergize with the temporal process of tumor immunoediting and physical microenvironmental stressors (such as hypoxia) to drive the formation and physical anchoring of these immune niches. Consequently, these structurally established domains mature into functionally distinct, heavily immunosuppressive hubs that foster local T-cell exhaustion and coordinated immune escape. Because these niches are dynamically evolving ecosystems rather than static entities, they present profound architectural barriers, directly contributing to the heterogeneous and often limited responses to current immunotherapies. By integrating these spatial and temporal dynamics into a comprehensive conceptual framework, this review highlights the urgent clinical need to shift toward multidimensional, niche-disrupting therapeutic strategies, ultimately aiming to improve immunotherapy efficacy and clinical outcomes for patients with brain tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786221","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":"Amplification of seeding-competent tau aggregates by PMCA in human and experimental tauopathies.","authors":"Florian Almela, Maxime Belondrade, Raphaelle Caillierez, Sarah Leclercq, Thomas Bouillet, Séverine Bégard, Marie Oosterlynck, Sabiha Eddarkaoui, Susana Boluda, Luc Buée, Simon Nicot, Morvane Colin, Daisy Bougard","doi":"10.1186/s40478-026-02345-4","DOIUrl":"https://doi.org/10.1186/s40478-026-02345-4","url":null,"abstract":"<p><p>Tau assemblies, associated with tauopathies, are believed to self-propagate through prion-like mechanisms in the central nervous system, driving neurodegeneration. Recently, protein seed amplification assays have emerged as highly sensitive methods for detecting trace amounts of misfolded protein assemblies across various neurodegenerative diseases. In this study, we utilized protein misfolding cyclic amplification (PMCA) to demonstrate that tau assemblies from the brains of transgenic mice or human patients with tauopathies can be efficiently amplified. Amplification was achieved using complex matrix substrates, such as brain homogenates or cell lysates expressing aggregation-prone mutant tau proteins, with heparin as a cofactor. This assay enabled the highly sensitive detection of tau assemblies, even at 1-million-fold dilutions of brain homogenate from aged and symptomatic THY-Tau30 transgenic mice (a model of tauopathy) and human cases of frontotemporal lobar degeneration (FTLD-P301L). Tau assemblies from Alzheimer's disease (AD) patients were also successfully amplified, albeit with lower sensitivity compared to other tauopathies. Critically, the PMCA-generated tau assemblies retained seeding competence, inducing further tau aggregation in reporter tau \"biosensor\" cells and in young THY-Tau30 mice following intracerebral injection. Together, our findings establish PMCA as an in vitro model for studying the seeded aggregation of tau assemblies, providing a powerful tool to advance research into tau aggregation mechanisms and the development of therapeutic interventions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762877","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":"Galectin-3 is elevated in Müller glia in human glaucomatous eyes and ocular hypertensive rat eyes and associated with phagocytosing states.","authors":"Anne Rombaut, Luozixian Wang, Emma Lardner, Raymond Cb Wong, Charlotte Taul, Miriam Kolko, Gustav Stålhammar, Rune Brautaset, Filippo Locri, Pete A Williams, James R Tribble","doi":"10.1186/s40478-026-02388-7","DOIUrl":"10.1186/s40478-026-02388-7","url":null,"abstract":"<p><p>Glaucoma is a leading cause of irreversible blindness worldwide, yet available treatments fail to prevent disease progression for all patients. It is characterized by a progressive dysfunction and loss of retinal ganglion cells. Neuroinflammation has been recognized as an underlying neurodegenerative mechanism of glaucoma in animal models and human post-mortem samples, and targeting neuroinflammation may provide additional means to neuroprotection. Galectin-3, a pro-inflammatory mediator encoded by the LGALS3 gene in humans, holds promise as a treatable target as its pharmacological and genetic inhibition is neuroprotective in multiple models of experimental glaucoma. However, the role of Galectin-3 in glaucoma remains unclear, particularly whether its emergence is a consequence of degeneration, or occurs at earlier time points. To address these knowledge gaps, we labeled IBA1, GFAP, and Galectin-3 in retina sections at early glaucoma stages in the rat bead glaucoma model, and in human retina from glaucoma donors. In the rat, IBA1 volume, but not GFAP, increased at an early, pre-degenerative timepoint. Accompanying this, we identified a significant increase of Galectin-3/IBA1 colocalization compared to control at the same timepoint, supporting the upregulation of Galectin-3 in early inflammation, preceding retinal ganglion cell degeneration in experimental glaucoma. However, a significant increase in Galectin-3/GFAP colocalization compared to control at the same timepoint in the rat additionally associates Galectin-3 production with astrocytes and Müller glia. This Galectin-3 to Müller glia relationship was significantly pronounced in human glaucomatous retina, predominating over microglia co-labelling. We further demonstarted that human MIO-M1 Müller glia in vitro express Galectin-3, but this is not altered in response to glaucoma relevant stimuli (TNF-α or mild-metabolic stress from rotenone). Instead, Galectin-3 expression was altered in phagocytosing states from exposure to E. coli particles, brain synaptosomes, or apoptotic neuronal debris. These findings provide further insight into Galectin-3 and gross inflammatory responses in glaucoma pathology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672677","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":"Overactive EAAT1 Cl^- channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia.","authors":"Yulia Kostritskaia, Daniela Bulla-Miely, Miriam Engels, Jan Meyer, Juliane L Berns, Sabrina Behuet, Sebastian Bludau, Christine R Rose, Albert Becker, Thomas Gensch, Ulrike B S Hedrich, Christoph Fahlke, Peter Kovermann","doi":"10.1186/s40478-026-02399-4","DOIUrl":"10.1186/s40478-026-02399-4","url":null,"abstract":"<p><p>A missense variant in SLC1A3, which results in a proline to arginine substitution in the glial excitatory amino acid transporter 1 (EAAT1), causes a severe form of episodic ataxia type 6, characterized by recurrent attacks of ataxia and epilepsy. EAATs are dual function transport proteins, and the P290R variant reduces secondary active glutamate transport rates, while enhancing the anion channel activity. Here, we used complementary electrophysiological, imaging, biochemical and neuropathological techniques to characterize the cellular mechanisms underlying epileptic seizures in a mouse model of episodic ataxia type 6, the heterozygous Slc1a3^P290R/+ mouse. Video-EEG recordings demonstrate frequent and severe spontaneous epileptic seizures in vivo. \"Gliosis only\" phenotype in the cerebrum of Slc1a3^P290R/+ mice, which was restricted to the hippocampal formation, suggests that this brain structure may be involved in the development of epileptic seizure activity. Electrophysiological recordings from acute slices revealed a reduction in tonic GABAergic transmission in Slc1a3^P290R/+ dentate gyrus granule cells, and to a lesser extent in cortical layer 2/3 pyramidal neurons before seizure onset. Phasic GABAergic and glutamatergic transmission remained unaltered in juvenile animals of the same developmental stage. There was no difference in expression levels of the GABA_A receptor (GABA_AR) δ subunits, suggesting that impaired tonic inhibition results from decreased extrasynaptic GABA concentrations. We identified enhanced GABA uptake by hippocampal radial glia-like cells (RGLs), caused by elevated GABA transporter 3 (GAT-3) expression and by an increased GABA transport driving force-due to lower intracellular chloride levels [Cl^-]_int - as cellular basis of impaired tonic inhibition. Our study demonstrates how increased EAAT1 chloride channel activity of the P290R variant can cause hyperexcitability by modifying synaptic GABA concentrations, while impaired EAAT1 glutamate transport leaves glutamatergic synaptic transmission in Slc1a3^P290R/+ mice unaffected.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683093","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":"Cell-free DNA methylation profiling reveals injury types and severities in swine rotational and contusional models of traumatic brain injury.","authors":"Shih-Han Kao, Larry N Singh, Sanjeev Chawla, Hunter A Gaudio, Kevin D Browne, Samuel S Shin, Lucas J Hobson, Sarah Kenna, Jonathan Starr, M Katie Weeks, Nicholas J Widmann, Anthony M Davis, Takayuki Sueishi, Karli Wulwick, Jenna Sittineri, D Kacy Cullen, Todd J Kilbaugh","doi":"10.1186/s40478-026-02384-x","DOIUrl":"https://doi.org/10.1186/s40478-026-02384-x","url":null,"abstract":"<p><p>Early diagnosis of traumatic brain injury (TBI) is crucial to guide treatment and improve recovery. Yet neuroimaging-the current gold standard for detection-cannot detect subtle biochemical changes and is insufficient to diagnose many TBI cases. Consequently, there is an urgent need for early, brain-associated biomarkers of TBI. Following injury, brain cells release cell-free DNA (cfDNA) into peripheral blood due to neurovascular disruption. DNA methylation patterns, which inform tissue specificity, could serve as biomarkers for TBI severity and progression. To test this hypothesis, we analyzed cfDNA from peripheral blood of swine models of TBI having injuries of differing severity and type: mild and moderate contusional, and mild and moderate rotational injuries. Using whole genome bisulfite sequencing, we identified distinct brain-associated cfDNA epigenetic signatures of affected brain regions, and the underlying biological processes associated with each injury type and severity. In these brain regions, proton magnetic resonance spectroscopic imaging (¹H MRSI) independently confirmed changes in biomarkers of brain health and function (choline and N-acetylaspartate metabolites). Droplet digital PCR validated that cfDNA differentially methylated regions (DMRs) tracked TBI progression. Our findings provide evidence that brain-associated cfDNA methylome signatures, combined with ¹H MRSI, can characterize the neurobiological processes at sites of TBI in a preclinical model. These results support further investigation of cfDNA as a non-invasive biomarker for TBI detection and monitoring, pending validation in larger and clinically diverse cohorts.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102559","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":"Time-dependent prognostic value of automated Ki67 assessment and its integration with molecular risk profiling in WHO grade 2 meningioma.","authors":"Luisa Voßbeck, Felix Ehret, Eilis Perez, Helena Radbruch, Elisabeth G Hain, Simone Schmid, Julia Onken, Merten Bohn, Nabiha Salman, Leonille Schweizer, David Capper, Moritz Armbrust, David Kaul","doi":"10.1186/s40478-026-02387-8","DOIUrl":"10.1186/s40478-026-02387-8","url":null,"abstract":"<p><p>WHO grade 2 meningiomas exhibit highly heterogeneous clinical courses. While the Ki67 proliferation index is a standard biomarker, its prognostic utility remains limited by methodological inconsistency and potential time-dependent dynamics. We evaluated an automated, artifact-adjusted Ki67 assessment and its integration with molecular risk profiling. 98 WHO grade 2 meningiomas (WHO 2021) were analyzed using an automated QuPath-based pipeline with HistoART for artifact exclusion. Molecular risk was defined by methylation and copy number profiling to calculate the integrated molecular-morphologic risk score by Maas et al. We employed extended Cox models to account for proportional hazards violations. Automated Ki67 values were significantly lower than routine pathological estimates (median 2.91% vs. 10%; p < 0.001) and correlated modestly with integrated risk scores (ρ = 0.26, p = 0.009). We identified a biphasic risk pattern: within the first 38 postoperative months, an automated Ki67 > 3.62% was a strong independent predictor for local recurrence (HR 5.06, p < 0.001) and progression-free survival (HR 4.15, p = 0.002), remaining significant alongside subtotal resection and the integrated risk group. Beyond 38 months, prognostic impact attenuated. Ki67 and the integrated molecular risk score contributed independently in multivariable models, suggesting complementary biological dimensions. Automated, artifact-adjusted Ki67 quantification provides time-dependent, independent prognostic information in WHO grade 2 meningioma, complementary to molecular risk stratification. It may serve as a cost-effective surveillance marker-both as an adjunct to molecular profiling and as a standalone tool where molecular testing is unavailable.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597643","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":"Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.","authors":"Lovleen Garg, Kriti Chaplot, Gowhith Kuppili, Shweta Tendulkar, Jomon Joseph, Siddhesh Kamat, Girish Ratnaparkhi","doi":"10.1186/s40478-026-02391-y","DOIUrl":"10.1186/s40478-026-02391-y","url":null,"abstract":"<p><p>Membrane Contact sites (MCS) have emerged as physiologically relevant zones that coordinate inter-organelle communication and cellular function. VAPB, an ER-resident MCS tethering protein, plays a central role in regulating MCSs through its numerous protein interactors, thereby influencing cellular homeostasis. A pathogenic missense VAPB^P56S mutation causes familial Amyotrophic Lateral Sclerosis 8 (ALS8) in humans, with progressive degeneration of motor neurons. The precise mechanisms underlying the motor neurodegeneration remain poorly understood. In this study, we examine lipid imbalance in the brain of a Drosophila model of ALS8 (VAPB^P58S). Specifically, we find that lipid homeostasis is disrupted in an age-dependent manner. Strikingly, cholesterol esters and sphingolipids show an age-dependent increase, while cholesterol shows a decrease. Intriguingly, from a cellular perspective, despite the accumulation of triacylglycerols (TAGs) in the brains of VAPB^P58S animals, the increased neutral lipid species do not correlate with lipid droplets (LDs), which are fewer in density and smaller in size. Lipid imbalance and progressive motor dysfunction in VAPB^P58S animals can be reversed by expressing VAPB^WT, suggesting a relationship between VAPB activity and lipid flux. To uncover VAPB's role in lipid homeostasis, we modulate VAPB activity in neurons and glia to dissect out tissue-specific roles. We find that both cell types contribute to lipid homeostasis in differential ways. In glia, LD flux is strongly dependent on VAPB activity, a dependence further recapitulated in cultured human cell lines, suggesting evolutionary conservation of the regulatory mechanism. Thus, we hypothesize that lipid dysregulation constitutes a critical pathogenic feature of ALS8, with the VAPB^P56S allele disrupting lipid homeostasis in the neuro-glial axis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001034","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":"De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.","authors":"Alison Mao, Alejandro Ruiz-Riquelme, Marim M Barghash, Nicholas R G Silver, Heather H C Lau, Erica Stuart, Silvia Zampar, Dag Sehlin, Stina Syvänen, Michael S Pollanen, K Peter R Nilsson, Caroline Graff, Martin Ingelsson, Joel C Watts","doi":"10.1186/s40478-026-02390-z","DOIUrl":"https://doi.org/10.1186/s40478-026-02390-z","url":null,"abstract":"<p><p>In familial Alzheimer's disease (FAD), mutations in the amyloid precursor protein gene (APP) accelerate the aggregation of Aβ peptide, leading to deposition of amyloid plaques within the brain. Conformational variants of Aβ aggregates (\"Aβ strains\") possess distinct pathological properties and may contribute to disease heterogeneity. While the Swedish APP mutation produces wild-type (WT) Aβ, the Arctic APP mutation generates E22G-mutant Aβ. To clarify whether different FAD mutations are sufficient to specify the formation of distinct Aβ strains, we performed Aβ seeding studies in App^NL-F knock-in mice. Aβ aggregates purified from Swedish and Arctic FAD human brains induced distinct neuropathological signatures, characterized by differences in the morphology and localization of the seeded Aβ deposits, which were preserved upon serial passage. Neither synthetic E22G-mutant Aβ aggregates nor Aβ aggregates isolated from the brains of transgenic mice producing E22G-mutant Aβ recapitulated the phenotype induced by Arctic FAD brain-derived Aβ aggregates upon injection into App^NL-F mice. Similarly, neither synthetic WT Aβ aggregates nor Aβ aggregates from Swedish APP-mutant transgenic mice reproduced the seeding behavior of Swedish FAD brain-derived Aβ aggregates. This suggests that it is the structure of Aβ aggregates rather than the Aβ sequence that dictates seeding activity. We conclude that de novo formation of FAD-relevant Aβ strains occurs exclusively in the human brain, implying the existence of human brain-specific cofactors that modulate Aβ aggregate structure and seeding activity.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222963","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":"Methylation profiling and alternative classification approaches in a glioma-enriched FFPE stereotaxic biopsy cohort.","authors":"Katharina Johanna Weber, Jürgen Hench, Markus Zumpt, Thomas Eska, Moritz Armbrust, Pia Susann Zeiner, Tabea Isabelle Hartung, Viktoria Ruf, Eike Steidl, Mareike Dettki, Tim Fenton, Joachim Peter Steinbach, Marcus Czabanka, David Capper, Stephan Frank, Karl-Heinz Plate, Marie-Thérèse Forster, Patrick Nikolaus Harter","doi":"10.1186/s40478-026-02382-z","DOIUrl":"10.1186/s40478-026-02382-z","url":null,"abstract":"<p><p>DNA methylation profiling of CNS tumors supports and refines histological diagnoses. Tumor DNA methylation signatures allow for an alignment with reference methylation classes and copy number profiling required for molecular grading. Overall, and especially in cases with limited tissue like in stereotaxic (STX) biopsies, there is a need for informed triage to most promising analysis techniques. Here, we investigated the diagnostic potential and accuracy of DNA methylation profiling and molecular grading in STX samples. FFPE samples of 237 patients were subjected to DNA methylation analysis including the Heidelberg (v11b4), Bethesda (v2) and EpiDiP brain tumor classifiers, copy number profiling and tumor deconvolution using MethylCIBERSORT. 90.5% of samples (n = 232) were allocated DNA methylation classes, with 61.6% reaching Heidelberg classifier scores of > 0.84. Indicatory copy number variations (CNVs) were detectable in 96.9% of cases. Recursive partitioning supported by a resampling-based validation with repeated random subsampling pointed towards brain tumor classifier dependent minimum analyte inputs to reach robust calibrated scores for DNA methylation class allocation. Successful integrative diagnostics furthermore depended on pre-classifier H&E diagnoses with 96.2% of H&E malignant diffuse gliomas, 91.5% of H&E diffuse gliomas but only 60% of H&E circumscribed gliomas classifiable using the Heidelberg brain tumor classifier. When the alternative classifiers EpiDiP and Bethesda were used, higher DNA input amounts ameliorated the classification robustness. Nevertheless, diagnostics of high-grade gliomas in midline location and lower-grade glial/glioneuronal tumors posed a challenge. Our findings demonstrate the broad applicability of DNA methylation profiling and molecular grading to small brain tumor specimens under the caveat of certain tumors and locations potentially benefiting from additional molecular as well as computational approaches to increase methylation signals relevant for classification in the future.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560504","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":"Gene supplementation therapy restores motor deficits in Gnao1[C215Y] mice and proves broad efficacy in C. elegans model.","authors":"Germana Cocozza, Tiziano D'Andrea, Martina Di Rocco, Ludovica Maria Busdraghi, Gilda Chilà, Xingzi Lin, Enrico Lanza, Fanny Collaud, Francesca C Follo, Clelia Buccheri, Viola Folli, Giuseppe Ronzitti, Ferdinando Scavizzi, Marcello Raspa, Vincenzo Leuzzi, Vladimir L Katanaev, Serena Galosi, Sergio Fucile, Simone Martinelli, Giuseppina D'Alessandro, Cristina Limatola","doi":"10.1186/s40478-026-02389-6","DOIUrl":"10.1186/s40478-026-02389-6","url":null,"abstract":"<p><p>The heterotrimeric G proteins are ubiquitous membrane-bound complexes specialized in the transduction of receptor-mediated extracellular signals into intracellular responses. Mutations in the G protein subunit alpha O1 (Gαo), encoded by GNAO1, have been associated with neurodevelopmental disorders characterized by prominent movement disorder with or without epilepsy. The Gnao1[C215Y]/+ mouse model recapitulates key features of the human disease, with a relatively mild phenotype, normal viability and late onset movement abnormalities, detectable in specific motor tasks. Here we report functional alterations in cortical layer V pyramidal neurons from Gnao1[C215Y]/+ mice, with reduction of the inward currents (Ih) and impairment of the GABAB-mediated outward current. We propose an adeno-associated virus (AAV)-based gene therapy aimed at overexpressing the wild-type form of Gαo by intracerebroventricular injection in newborn heterozygous Gnao1[C215Y]/ + mice. Our results demonstrate that overexpression of the wild-type protein mitigates behavioral abnormalities and restores functional neuronal deficits in young adult mice, thereby supporting the development of AAV-mediated gene augmentation strategies to counteract the effects of GNAO1 variants in patients. The potential of gene supplementation therapy is further supported by data from genetically modified C. elegans strains carrying not only the relatively mild C215Y variant but also a panel of goa-1/GNAO1 mutations associated with more severe phenotypes, suggesting a broader potential of this therapeutic strategy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547497","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}