Acta Neuropathologica Communications最新文献

{"title":"Acquired neuropathology and its associations with key patterns of placental pathology.","authors":"Angela N Viaene, Jasmine Steele, Rebecca L Linn","doi":"10.1186/s40478-025-02065-1","DOIUrl":"10.1186/s40478-025-02065-1","url":null,"abstract":"<p><p>Perinatal brain injury is a major cause of neurodevelopmental disability worldwide. Placental pathology has been implicated as a likely cause of injury to the developing central nervous system (CNS). This study aims to elucidate the associations of multiple placental pathologies and CNS injury, including more subtle brain pathologies associated with adverse neurologic outcomes. Sixty-five subjects that underwent complete post-mortem neuropathologic examination and placental examination were selected for inclusion. Gross images, autopsy reports, and histologic sections from the CNS and placenta underwent blinded reviewed by experts in perinatal neuropathology and placental pathology, respectively. Immunostains useful in highlighting CNS lesions not apparent on routine histologic sections were performed. Placental pathology was classified according to the Amsterdam criteria, and all placental and CNS abnormalities were documented. A previously undescribed association between white matter injury and fetal vascular malperfusion was seen, likely due to improved detection of injury on immunohistochemical stains. Amniotic fluid infection was associated with acute neuronal injury in the cortex and cerebellum as well as subarachnoid hemorrhage. Hippocampal injury had the strongest association with high-grade chronic inflammation, and maternal vascular malperfusion showed higher relative frequencies of acute neuronal injury in the basal ganglia, brainstem, and spinal cord. To our knowledge, this is the first study to standardize placental pathology according to the Amsterdam consensus criteria, separate out injury across multiple CNS regions with independent assessment of these regions, and to utilize immunohistochemistry to improve detection of white matter injury. Different patterns of placental pathology were associated with different types of CNS injury, indicating neuronal injury and white matter injury may be influenced by distinct placental pathologies. Elucidating the placental contributions to these acquired CNS pathologies in stillborns is crucial for understanding long-term adverse neurodevelopmental outcomes associated with perinatal brain injury.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"138"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525830","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":"C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.","authors":"Lilian Tsai-Wei Lin, Marc Shenouda, Philip McGoldrick, Agnes Lau, Janice Robertson","doi":"10.1186/s40478-025-02061-5","DOIUrl":"10.1186/s40478-025-02061-5","url":null,"abstract":"<p><p>Cytoplasmic aggregates of the predominantly nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases caused by G₄C₂ hexanucleotide repeat expansions in C9orf72 (C9-ALS/FTD). While these repeat expansions are associated with both gain- and loss-of-function mechanisms, the contribution of C9orf72 loss of function to disease pathogenesis remains unclear. C9orf72 has been shown to regulate autophagy, and its deficiency has been shown to exacerbate phenotypes in gain-of-function G₄C₂ models, implicating impaired autophagic clearance in disease pathogenesis. Here, we directly test whether C9orf72 deficiency exacerbates TDP-43 pathology and neurodegeneration in vivo. Using AAV9-vectors to drive neuron-specific expression of pathologically relevant C-terminal species of TDP-43, TDP-35 and TDP-25, we established models of TDP-43 pathology that recapitulate key disease features, including cytoplasmic aggregates, motor and cognitive decline, and neuronal loss. TDP-25 expression in particular produced robust, abnormally phosphorylated, ubiquitinated and p62-labelled cytoplasmic aggregates, modelling TDP-43 pathology in disease. Loss of C9orf72 in TDP-25-expressing mice accelerated the onset of motor deficits, increased neurodegeneration, and impaired the autophagic response to TDP-25 expression. These findings reveal that C9orf72 deficiency disrupts autophagy and exacerbates TDP-25-mediated toxicity in vivo, supporting a contributory role for C9orf72 loss-of-function in driving neurodegeneration in C9-ALS/FTD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"136"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525831","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":"Ultra-low-input cell-free DNA sequencing for tumor detection and characterization in a real-world pediatric brain tumor cohort.","authors":"Tom T Fischer, Kendra K Maaß, Pitithat Puranachot, Markus Mieskolainen, Martin Sill, Paulina S Schad, Stefanie Volz, Fabian Rosing, Tatjana Wedig, Nathalie Schwarz, Agnes M E Finster, Florian Iser, Jochen Meyer, Felix Sahm, Olli Lohi, Ahmed El Damaty, Benedikt Brors, Hannu Haapasalo, Stefan M Pfister, Joonas Haapasalo, Kristian W Pajtler, Kristiina Nordfors","doi":"10.1186/s40478-025-02024-w","DOIUrl":"10.1186/s40478-025-02024-w","url":null,"abstract":"<p><p>Molecular profiling of pediatric central nervous system (CNS) tumors has important clinical utility for guiding diagnostic and therapeutic strategies. Cell-free DNA (cfDNA) from liquid biopsies has been used for minimally invasive tumor profiling and longitudinal disease assessment in adult oncology and pediatric hematology. However, in pediatric neuro-oncology, low cfDNA yields pose a major barrier to translating these assays from bench to bedside. Here, we implemented a low-coverage whole genome sequencing (lcWGS) assay for picogram-level cfDNA inputs and applied it to liquid biopsies from a sizeable, population-based, cross-entity pediatric CNS tumor cohort (n = 56 patients). Applying this protocol, cfDNA whole genome profiles were successfully acquired from all liquid biopsy samples (n = 61/61 serum, n = 56/56 CSF, 100%). Based on copy number variations (CNVs), circulating-tumor DNA (ctDNA) was detected in 2/61 serum (3%) and in 25/56 CSF (45%) samples across various brain tumor entities. The integration of cfDNA results with clinical data demonstrated the utility of CSF lcWGS as a biomarker assay at diagnosis to distinguish cancerous from non-cancerous pineal region lesions (n = 6 patients). Additionally, serial CSF assessment in n = 9 patients (n = 29 CSF samples) enabled minimally invasive disease monitoring, with the added value of molecular profile availability in n = 4/6 (67%) patients at relapse. Proof-of-concept data show the feasibility of serial CSF lcWGS to reveal tumor evolution, tumor heterogeneity and potential therapeutic vulnerabilities in a case of medulloblastoma and germ cell tumor. Our study underscores the clinical utility of a robust lcWGS-based liquid biopsy assay optimized for low-input samples. We identify use-cases for implementing liquid biopsies in the clinical management of pediatric CNS tumor patients and provide a strong rationale for integration into future trials.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"134"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511396","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":"Co-occurrence of myositis and neuropathy after anti-CD30 therapy in a late-adolescent Hodgkin lymphoma patient.","authors":"Adela Della Marina, Lydia Rink, Andreas Hentschel, Michael M Schündeln, Christopher Nelke, Heike Kölbel, Calvin Tucht, Vera Dobelmann, Tobias Ruck, Tim Hagenacker, Teresinha Evangelista, Ulrike Schara-Schmidt, Andreas Roos","doi":"10.1186/s40478-025-02056-2","DOIUrl":"10.1186/s40478-025-02056-2","url":null,"abstract":"<p><strong>Objective: </strong>Immune-related adverse events (irAEs) are recognized in oncology, particularly with immune checkpoint inhibitors and other targeted therapies. Brentuximab Vedotin (BV), is an anti-CD30 antibody-drug conjugate- its association with immune-mediated myositis remains unexplored. We report a case of an adolescent with Hodgkin lymphoma (HL) who developed neuropathy and myositis following BV therapy.</p><p><strong>Materials & methods: </strong>The diagnostic work-up included MRI as well as microscopic analyses (histology, electron microscopy, and immunostainings including CD30 and MxA) of a gastrocnemius muscle biopsy. Proteomic analysis was also performed on the same biopsy, and paradigmatic protein dysregulations were validated through immunostaining. Serum NCAM1 levels were measured using ELISA.</p><p><strong>Results: </strong>The patient, diagnosed with HL at 15 years, developed neuropathy after Vincristine treatment and was switched to BV. During BV therapy, she experienced progressive muscle weakness and foot drop, leading to discontinuation. MRI confirmed myositis, and biopsy revealed neurogenic and inflammatory changes with complement deposition and mitochondrial dysfunction. Proteomics showed upregulation of inflammatory relevant proteins, with HPRT1 (749.43-fold) being the most increased one. Intravenous immunoglobulin (IVIG) therapy improved muscle strength.</p><p><strong>Discussion: </strong>Myositis following BV therapy has not been reported. Findings suggest an immune-mediated mechanism with B-cell involvement. Given the response to IVIG, B-cell-directed therapies may be beneficial. This case identifies BV-induced myositis as a novel irAE.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"140"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525833","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":"Impaired splicing machinery in craniopharyngiomas unveils PRPF8 and RAVER1 as novel biomarkers and therapeutic targets.","authors":"Antonio C Fuentes-Fayos, Miguel E G-García, Teresa Sánchez-Medianero, John Apps, Álvaro Flores-Martínez, Ana S De la Rosa-Herencia, Ignacio Gil-Duque, Georg Otto, Eva Venegas-Moreno, Eugenio Cárdenas Ruiz-Valdepeñas, Aura D Herrera-Martínez, Juan Solivera, Manuel D Gahete, David A Cano, Rosa Ortega, Alfonso Soto-Moreno, María A Gálvez-Moreno, Juan Pedro Martínez-Barberá, Raúl M Luque","doi":"10.1186/s40478-025-02040-w","DOIUrl":"10.1186/s40478-025-02040-w","url":null,"abstract":"<p><p>Craniopharyngiomas are rare benign pathologies but clinically challenging tumours because of their intimate relationship with critical brain structures, leading to severe endocrine-deficiencies/comorbidities. Therefore, identifying alternative prognostic/therapeutic tools is crucial. Although dysregulated splicing is a molecular feature that characterizes almost all tumour/cancer types, the dysregulation of the components belonging to the molecular machinery controlling the splicing-process (spliceosome) remains unknown in craniopharyngiomas. Here, we uncover a profound dysregulation in the expression of relevant spliceosome-components and splicing-factors in craniopharyngiomas versus control non-tumour tissues, identifying PRPF8 and RAVER1 as key tumour suppressor factors associated with relevant oncogenic processes. Moreover, we demonstrate that the spliceosome activity inhibition using pladienolide-B in primary patient´s derived cell-cultures might serve as a potential therapeutic tool worth to be explored in humans. Altogether, our results demonstrate a drastic and clinically relevant spliceosome-associated molecular dysregulation in craniopharyngiomas, which could serve as a potential source of novel diagnostic/prognostic biomarkers and therapeutic targets.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"142"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525932","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":"Transcription factor-based classification of pituitary adenomas / PitNETs: a comparative analysis and clinical implications across WHO 2004, 2017 and 2022 in 921 cases.","authors":"Isabella Nasi-Kordhishti, Mirko Hladik, Kosmas Kandilaris, Felix Behling, Jürgen Honegger, Jens Schittenhelm","doi":"10.1186/s40478-025-02050-8","DOIUrl":"10.1186/s40478-025-02050-8","url":null,"abstract":"<p><p>The WHO classifications of 2017 and 2022 recommend the use of pituitary transcription factors PIT-1, T-PIT and SF-1 as well as GATA3 and ERα for histopathological diagnosis. The aim of this study is to demonstrate their diagnostic impact in a large retrospective cohort. 921 PitNETs/PAs diagnosed in our department between October 2004 and April 2018 were retrospectively reassessed according to the WHO classifications 2017 and 2022. The original classification (WHO 2004) and the clinical data were retrieved from the patient records. Hormone-immunonegative null cell adenomas represented the largest subgroup (397 of 921) in the WHO 2004 classification. Of these, 377 were reclassified as gonadotroph PitNETs/PAs, and 14 were assigned to a non-gonadotroph hormone-producing cell line. Only 6 cases remained null cell tumors. 27 of 35 plurihormonal adenomas were assigned to a specific cell line in the 2017 and 2022 WHO classifications. Of 489 adenomas formerly classified as expressing of 1 or 2 hormones, the histopathological diagnosis was confirmed in 459 cases with the use of TP. Of the remaining 30 cases, 12 cases with positive immunostaining of 2 hormones could be assigned to a single cell line, and 18 cases changed their lineage. The correct correlation with clinical data significantly improved from 75.4% (WHO 2004) to 96.2% (WHO 2017 and 2022). Corticotroph PitNETs showed the highest risk for recurrence (21.9%) and progression (55.8%). The new classification enables more accurate (sub)classification and significantly improves clinicopathological correlation. In individual cases, it is essential to consider the reclassification to predict the clinical prognosis and to schedule the follow-up accordingly.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"135"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511395","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":"MYC promotes group 3 medulloblastoma cell proliferation and alleviates ROS-induced cell death by upregulating transketolase.","authors":"Shizun Wang, Dan Zhang, Chunlong Wang, Yuqin Liu","doi":"10.1186/s40478-025-02051-7","DOIUrl":"10.1186/s40478-025-02051-7","url":null,"abstract":"<p><p>Medulloblastoma is a common embryonic malignant tumor in children. Patients with Group 3 medulloblastoma exhibit the poorest prognosis among all subgroups, and approximately 20% of these patients carry an amplification of MYC. Metabolic reprogramming, a hallmark of cancer, includes the pentose phosphate pathway (PPP) as a branch of glucose metabolism, providing cells with ribose-5-phosphate (R5P) and nicotinamide adenine dinucleotide phosphate (NADPH). The role of PPP in medulloblastoma remains unclear. In this study, we utilized transcriptomic data to identify that high expression of transketolase (TKT) correlates with worse overall survival (OS) in Group 3 patients. We found that TKT promotes proliferation of Group 3 medulloblastoma cell line cells both in vitro and in vivo. Additionally, TKT enhances R5P synthesis, increasing the proportion of S-phase cells and promoting proliferation. TKT also facilitates NADPH synthesis, which reduces intracellular reactive oxygen species (ROS) levels, inhibits ROS-induced cell death, and strengthens cellular resistance to ROS-induced injury. Subsequently, we demonstrated that inhibition of MYC leads to decreased TKT protein levels, and MYC promotes cell proliferation and suppresses cell death via TKT. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction (ChIP-qPCR) confirmed that employing the antibody targeting MYC enables the immunoprecipitation of DNA localized to the promoter region of TKT. Using luciferase assay and western blot, we verified that MYC and specificity protein 1 (SP1) co-regulate the transcription of TKT and consequently elevates TKT protein levels. Collectively, our study reports that MYC facilitates the proliferation of Group 3 medulloblastoma cells and mitigates ROS-induced damage through TKT, suggesting TKT as a potential therapeutic target for MYC-driven Group 3 medulloblastoma.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"139"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525933","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":"Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.","authors":"Benjamin Lin, Abigail K Shelton, Erin Smithberger, Julia Ziebro, Kasey R Skinner, Ryan E Bash, Richard Kirkman, Allie Stamper, Madison Butler, Alex Flores, Steven P Angus, Michael P East, Timothy F Cloughesy, David A Nathanson, Michael E Berens, Jann N Sarkaria, Zev A Binder, Donald M O'Rourke, Timothy C Howton, Brittany N Lasseigne, Christopher D Willey, Gary L Johnson, Anita B Hjelmeland, Frank B Furnari, C Ryan Miller","doi":"10.1186/s40478-025-02068-y","DOIUrl":"10.1186/s40478-025-02068-y","url":null,"abstract":"<p><p>GBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM. Upfront combinatorial therapy featuring EGFR tyrosine kinase inhibitors (TKI) may overcome these challenges. To identify combinatorial drug targets within the kinome, we temporally characterized drug-induced kinome rewiring in isogenic, genetically engineered Cdkn2a-deleted mouse astrocytes expressing human EGFRvIII. We utilize RNA sequencing and multiplex inhibitor beads, coupled with mass spectrometry, to demonstrate that kinome rewiring exhibits both shared and unique kinases after acquired resistance develops to EGFR TKI, despite using models with a common genetic background. Additionally, we noted that kinases altered in the acute setting are distinct from those in acquired resistance. By identifying kinome vulnerabilities throughout the acute, dynamic drug response process, we generated a kinase signature associated with EGFR inhibition. Further molecular interrogation of signature genes revealed that drug treatment induces an unexpected increase in Cdk6 protein, but not mRNA, despite live cell imaging and transcriptomic evidence indicating decreased proliferation. Survival experiments with orthotopic allografts show that upfront combination inhibition of Cdk6, using abemaciclib, and EGFR, using neratinib, significantly prolonged median survival compared to neratinib alone. Our findings suggest that identifying and inhibiting targets with synthetic lethality in the upfront combinatorial setting is a viable approach for precision oncology and may help provide an avenue to overcome the resistance mechanisms that contributed to the failures of EGFR as a molecular target in GBM.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"143"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525931","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":"Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model.","authors":"Benjamin D Rowlands, Benjamin G Trist, Connor Karozis, Greta Schaffer, David Mor, Richard Harwood, Sarah A Rosolen, Veronica Cottam, Freyja Persson-Carboni, Miriam Richardson, Anne A Li, Michael P Gotsbacher, Amr H Abdeen, Rachel Codd, Kay L Double","doi":"10.1186/s40478-025-02048-2","DOIUrl":"10.1186/s40478-025-02048-2","url":null,"abstract":"<p><p>Misfolded wild-type superoxide dismutase 1 (disSOD1) protein is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated whether the blood-brain-barrier-permeable copper delivery drug, CuATSM, attenuated the misfolding and deposition of wild-type disSOD1 and associated neuron death in a novel mouse model that expresses this pathology. These factors were profiled using proteomic and elemental mass spectrometry, together with biochemical and histological workflows. We demonstrated copper supplementation corrects altered post-translational modifications on soluble SOD1 and improves the enzymatic activity of the protein in the brains of these animals. These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. Our data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"133"},"PeriodicalIF":6.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493319","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":"Robust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing.","authors":"Dean Thompson, Jemma Castle, Martin Sill, Stefan M Pfister, Simon Bailey, Debbie Hicks, Steven C Clifford, Edward C Schwalbe","doi":"10.1186/s40478-025-02049-1","DOIUrl":"10.1186/s40478-025-02049-1","url":null,"abstract":"<p><p>Medulloblastoma comprises four principal molecular disease groups and their component subgroups, each with distinct molecular and clinical features. Group assignment is currently achieved diagnostically using Illumina DNA methylation microarray. Whole-genome sequencing (WGS) capacity is rapidly expanding in the clinical setting and the development of platform-independent, sequence-based assays of molecular group offers significant potential. Specifically, whole-genome bisulfite sequencing (WGBS) enables assessment of genome-wide methylation status at single-base resolution, however its routine application has been limited by high DNA input requirements, cost, and a lack of pipelines tailored to more rapidly-acquired and cost-effective low-depth (< 10x) sequencing data. We utilised WGBS data for 69 medulloblastomas, comprising 35 in-house low-depth (~ 10x) and 34 publicly available high-depth (~ 30x) samples, alongside cerebellar controls (n = 8), all with matched DNA methylation microarray data. We assessed quality (QC) and imputation approaches using low-pass WGBS data, assessed inter-platform correlation and identified molecular groups and subgroups by directly integrating matched/associated loci from WGBS sample data with the MNP classifier probeset. We further assessed and optimised reference-free aneuploidy detection using low-pass WGBS and assessed concordance with microarray-derived calls. We developed and optimised pipelines for processing, QC, and analysis of low-pass WGBS data, suitable for routine molecular subgrouping and reference-free aneuploidy assessment. We demonstrate that low-pass WGBS data can (i) be integrated into existing array-trained models with high assignment probabilities for both principal molecular groups (97% concordance) and molecular subgroups (94.2% concordance), and (ii) detect clinically relevant focal copy number changes, including SNCAIP, with greater sensitivity than microarray approaches. Low-pass WGBS performs equivalently to array-based methods at comparable cost. Finally, its ascertainment of the full methylome enables elucidation of additional biological complexity and inter-tumoural heterogeneity that has hitherto been inaccessible. These findings provide proof-of-concept for clinical adoption of low-pass WGBS, applied using standard WGS technology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"132"},"PeriodicalIF":6.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482820","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}