Acta Neuropathologica Communications最新文献

{"title":"Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei.","authors":"Vasileios Theologidis, Sara A Ferreira, Nanna M Jensen, Diana Gomes Moreira, Ole A Ahlgreen, Mads W Hansen, Emilie D Rosenberg, Mette Richner, Islam Faress, Hjalte Gram, Poul Henning Jensen, Per Borghammer, Jens R Nyengaard, Marina Romero-Ramos, Christian B Vægter, Wilma D J van de Berg, Nathalie Van Den Berge, Asad Jan","doi":"10.1186/s40478-025-01948-7","DOIUrl":"10.1186/s40478-025-01948-7","url":null,"abstract":"<p><p>α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in the brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN and distinct nuclei of subcortical motor system leads to progressive decline in home cage activity, which was accompanied by postural instability and impaired motor coordination. The progressive accumulation of aSyn pathology in brainstem and motor neurons in lumbar spinal cord heralded the onset of a moribund stage, which culminated in impaired survival. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"32"},"PeriodicalIF":6.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439700","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":"Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease.","authors":"Miyah R Davis, Edward Robinson, Yosef Koronyo, Elena Salobrar-Garcia, Altan Rentsendorj, Bhakta P Gaire, Nazanin Mirzaei, Rakez Kayed, Alfredo A Sadun, Alexander V Ljubimov, Lon S Schneider, Debra Hawes, Keith L Black, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui","doi":"10.1186/s40478-025-01935-y","DOIUrl":"10.1186/s40478-025-01935-y","url":null,"abstract":"<p><p>Pathological tau isoforms, including hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and AD dementia. These patients exhibit significant retinal ganglion cell (RGC) loss, however the presence of tau isoforms in RGCs and their impact on RGC integrity, particularly in early AD, have not been studied. Here, we analyzed retinal superior temporal cross-sections from 25 MCI or AD patients and 16 age- and sex-matched cognitively normal controls. Using the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining, we found a 46-56% reduction in RBPMS⁺ RGCs and Nissl⁺ neurons in the ganglion cell layer (GCL) of MCI and AD retinas (P < 0.05-0.001). RGC loss was accompanied by soma hypertrophy (10-50% enlargement, P < 0.05-0.0001), nuclear displacement, apoptosis (30-50% increase, P < 0.05-0.01), and prominent expression of granulovacuolar degeneration (GVD) bodies and GVD-necroptotic markers. Both pS396-tau and Oligo-tau were identified in RGCs, including in hypertrophic cells. PS396-tau⁺ and Oligo-tau⁺ RGC counts were significantly increased by 2.1-3.5-fold in MCI and AD retinas versus control retinas (P < 0.05-0.0001). Tauopathy-laden RGCs strongly inter-correlated (r_P=0.85, P < 0.0001) and retinal tauopathy associated with RGC reduction (r_P=-0.40-(-0.64), P < 0.05-0.01). Their abundance correlated with brain pathology and cognitive deficits, with higher tauopathy-laden RGCs in patients with Braak stages (V-VI), clinical dementia ratings (CDR = 3), and mini-mental state examination (MMSE ≤   26) scores. PS396-tau⁺ RGCs in the central and mid-periphery showed the closest associations with disease status, while Oligo-tau⁺ RGCs in the mid-periphery exhibited the strongest correlations with brain pathology (NFTs, Braak stages, ABC scores; r_S=0.78-0.81, P < 0.001-0.0001) and cognitive decline (MMSE; r_S=-0.79, P = 0.0019). Overall, these findings identify a link between pathogenic tau in RGCs and RGC degeneration in AD, involving apoptotic and GVD-necroptotic cell death pathways. Future research should validate these results in larger and more diverse cohorts and develop RGC tauopathy as a potential noninvasive biomarker for early detection and monitoring of AD progression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"31"},"PeriodicalIF":6.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424468","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":"Blood biomarker fingerprints in a cohort of patients with CHRNE-related congenital myasthenic syndrome.","authors":"Adela Della Marina, Andrie Koutsoulidou, Daniel Natera-de Benito, Lars-Oliver Tykocinski, Marios Tomazou, Kristia Georgiou, Andreas Laner, Heike Kölbel, Andres Nascimento, Carlos Ortez, Angela Abicht, Basant Kumar Thakur, Hanns Lochmüller, Leonidas A Phylactou, Tobias Ruck, Ulrike Schara-Schmidt, Dipali Kale, Andreas Hentschel, Andreas Roos","doi":"10.1186/s40478-025-01946-9","DOIUrl":"10.1186/s40478-025-01946-9","url":null,"abstract":"<p><p>Mutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR - 483 - 3p, miR-365a-3p, miR - 365b - 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR - 205 - 5p, miR - 10b - 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR - 483 - 5p and decrease of miR - 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"29"},"PeriodicalIF":6.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412685","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":"The tumour microenvironment of pilocytic astrocytoma evolves over time via enrichment for microglia.","authors":"Thomas J Stone, Jessica C Pickles, Olumide Ogunbiyi, Shireena A Yasin, Catherine A Taylor, Saira W Ahmed, Jane Chalker, Carryl Dryden, Iwona Slodkowska, Emily Pang, Mark Kristiansen, Rachel Williams, Helena Tutill, Charlotte A Williams, Gaganjit K Madhan, Leysa Forrest, Tony Brooks, Mike Hubank, Debbie Hughes, Paula Proszek, Grzegorz Pietka, Erin Peat, Darren Hargrave, Thomas S Jacques","doi":"10.1186/s40478-024-01922-9","DOIUrl":"10.1186/s40478-024-01922-9","url":null,"abstract":"<p><p>Pilocytic astrocytoma (PA) is the commonest low-grade tumour affecting children and is frequently experienced as a chronic disease associated with extended treatment, periods of regrowth, and long-term disability. This contrasts with the view of PA as a benign tumour with positive clinical outcomes and raises the fundamental question of biologically driven change over time within these tumours, which will impact diagnosis, stratification, and management. To investigate the molecular, cellular, and pathological stability of PA we performed RNA sequencing, methylation array profiling, immunohistochemistry, and targeted panel DNA sequencing on a cohort of 15 PA patients with matched primary/longitudinal samples at a mean sampling interval of 2.7 years. Through pairwise analysis of primary versus longitudinal tumour samples we identified changes to immune-related pathways within the expression and methylation profiles of longitudinal PA. Further interrogation of these changes revealed an enrichment over time for microglial cell populations, which was validated by immunohistochemistry against common monocyte/microglial markers. Moreover, immunohistochemical characterisation revealed concurrent increases in the expression of M2-like and anti-inflammatory markers. Microglial enrichments were consistent across the cohort and were not adequately explained by a range of potential confounders, including receipt of adjuvant therapy. Taken together, these data challenge the idea of pilocytic astrocytoma as a static entity and indicate that they consistently accumulate microglia over time, potentially co-opting the immune microenvironment towards an anti-inflammatory phenotype that may affect the natural course and treatment response of the tumours.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"30"},"PeriodicalIF":6.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412699","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":"Disruption of mitochondrial homeostasis and permeability transition pore opening in OPA1 iPSC-derived retinal ganglion cells.","authors":"Michael Whitehead, Joshua P Harvey, Paul E Sladen, Giada Becchi, Kritarth Singh, Yujiao Jennifer Sun, Thomas Burgoyne, Michael R Duchen, Patrick Yu-Wai-Man, Michael E Cheetham","doi":"10.1186/s40478-025-01942-z","DOIUrl":"10.1186/s40478-025-01942-z","url":null,"abstract":"<p><p>Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the selective loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a dynamin-related GTPase protein. OPA1 plays a key role in the maintenance of the mitochondrial network, mitochondrial DNA integrity and bioenergetic function. However, our current understanding of how OPA1 dysfunction contributes to vision loss in DOA patients has been limited by access to patient-derived RGCs. Here, we used induced pluripotent stem cell (iPSC)-RGCs to study how OPA1 dysfunction affects cellular homeostasis in human RGCs. iPSCs derived from a DOA+ patient with the OPA1 R445H variant and isogenic CRISPR-Cas9-corrected iPSCs were differentiated to iPSC-RGCs. Defects in mitochondrial networks and increased levels of reactive oxygen species were observed in iPSC-RGCs carrying OPA1 R445H. Ultrastructural analyses also revealed changes in mitochondrial shape and cristae structure, with decreased endoplasmic reticulum (ER): mitochondrial contact length in DOA iPSC-RGCs. Mitochondrial membrane potential was reduced and its maintenance was also impaired following inhibition of the F1Fo-ATP synthase with oligomycin, suggesting that mitochondrial membrane potential is maintained in DOA iPSC-RGCs through reversal of the ATP synthase and ATP hydrolysis. These impairments in mitochondrial structure and function were associated with defects in cytosolic calcium buffering following ER calcium release and store-operated calcium entry, and following stimulation with the excitatory neurotransmitter glutamate. In response to mitochondrial calcium overload, DOA iPSC-RGCs exhibited increased sensitivity to opening of the mitochondrial permeability transition pore. These data reveal novel aspects of DOA pathogenesis in R445H patient-derived RGCs. The findings suggest a mechanism in which primary defects in mitochondrial network dynamics disrupt core mitochondrial functions, including bioenergetics, calcium homeostasis, and opening of the permeability transition pore, which may contribute to vision loss in DOA patients.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"28"},"PeriodicalIF":6.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412698","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":"Small molecule treatment alleviates photoreceptor cilia defects in LCA5-deficient human retinal organoids.","authors":"Dimitra Athanasiou, Tess A V Afanasyeva, Niuzheng Chai, Kalliopi Ziaka, Katarina Jovanovic, Rosellina Guarascio, Karsten Boldt, Julio C Corral-Serrano, Naheed Kanuga, Ronald Roepman, Rob W J Collin, Michael E Cheetham","doi":"10.1186/s40478-025-01943-y","DOIUrl":"10.1186/s40478-025-01943-y","url":null,"abstract":"<p><p>Bialleleic pathogenic variants in LCA5 cause one of the most severe forms of Leber congenital amaurosis, an early-onset retinal disease that results in severe visual impairment. Here, we report the use of gene editing to generate isogenic LCA5 knock-out (LCA5 KO) induced pluripotent stem cells (iPSC) and their differentiation to retinal organoids. The molecular and cellular phenotype of the LCA5 KO retinal organoids was studied in detail and compared to isogenic controls as well as patient-derived retinal organoids. The absence of LCA5 was confirmed in retinal organoids by immunohistochemistry and western blotting. There were no major changes in retinal organoid differentiation or ciliation, however, the localisation of CEP290 and IFT88 was significantly altered in LCA5 KO and patient photoreceptor cilia with extension along the axoneme. The LCA5-deficient organoids also had shorter outer segments and rhodopsin was mislocalised to the outer nuclear layer. We also identified transcriptomic and proteomic changes associated with the loss of LCA5. Importantly, treatment with the small molecules eupatilin, fasudil or a combination of both drugs reduced CEP290 and IFT88 accumulation along the cilia. The treatments also improved rhodopsin traffic to the outer segment and reduced mislocalisation of rhodopsin in the outer nuclear layer (ONL). The improvements in cilia-associated protein localisation and traffic were accompanied by significant changes in the transcriptome towards control gene expression levels in many of the differentially expressed genes. In summary, iPSC-derived retinal organoids are a powerful model for investigating the molecular and cellular changes associated with loss of LCA5 function and highlight the therapeutic potential of small molecules to treat retinal ciliopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"26"},"PeriodicalIF":6.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397574","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":"Neuropathological stages of neuronal, astrocytic and oligodendrocytic alpha-synuclein pathology in Parkinson's disease.","authors":"Maria Otero-Jimenez, Marcelina J Wojewska, Lawrence P Binding, Simona Jogaudaite, Sandra Gray-Rodriguez, Alexandra L Young, Steve Gentleman, Javier Alegre-Abarrategui","doi":"10.1186/s40478-025-01944-x","DOIUrl":"10.1186/s40478-025-01944-x","url":null,"abstract":"<p><p>Alpha-synucleinopathies are neurodegenerative diseases characterized by the spread of alpha-synuclein (α-syn) aggregates throughout the central nervous system in a stereotypical manner. These diseases include Lewy body disease (LBD), which encompass Dementia with Lewy bodies (DLB), Parkinson's Disease (PD), and Parkinson's Disease Dementia (PDD), and Multiple System Atrophy (MSA). LBD and MSA chiefly contain α-syn aggregates in neurons and oligodendrocytes, respectively, although glial α-syn pathology in LBD is increasingly being recognized. Semi-quantitative and machine learning-based quantifications of neuronal, oligodendrocytic and astrocytic α-syn pathology were implemented on a cohort of LBD and MSA post-mortem tissue samples. The neuroanatomical distribution of each cell-type specific α-syn pathology was evaluated using conditional probability matrices and Subtype and Stage Inference (SuStaIn) algorithm. We revealed extensive glial α-syn pathology in LBD, emphasizing the disease- and region-specific profile of astrocytic α-syn pathology, which was absent in MSA and minimal in the substantia nigra of LBD. Furthermore, we have described distinct morphologies of astrocytic α-syn pathology, which were found to correlate with the density of astrocytic α-syn inclusions. Astrocytic α-syn pathology was mainly centered in the amygdala and exhibited a unique stereotypical progression whilst oligodendrocytes displayed a distribution akin to the established neuronal progression pattern. SuStaIn modeling was further used to test for heterogeneity in the spatiotemporal progression, revealing that a subset of cases might follow an alternative pattern. Based on these findings, we introduce a novel multimodal progression framework that integrates, for the first time, the temporal and spatial progression of astrocytic and oligodendrocytic α-syn pathology alongside neuronal pathology in PD, providing further information regarding the role of neurons and glia in disease pathogenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"25"},"PeriodicalIF":6.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397563","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":"AQP4-specific T cells determine lesion localization in the CNS in a model of NMOSD.","authors":"Ali Maisam Afzali, Oleksii Ulianov, Luise Eckardt, Ingrid Stas, Lea Seeholzer, Katja Steiger, Doron Merkler, Thomas Korn","doi":"10.1186/s40478-025-01947-8","DOIUrl":"10.1186/s40478-025-01947-8","url":null,"abstract":"<p><p>Neuromyelitis optica spectrum disorder (NMOSD) is a paradigmatic autoimmune disease of the central nervous system (CNS), in which the water channel protein Aquaporin-4 (AQP4) is targeted by a self-reactive immune response. While the immunopathology of human NMOSD is largely dependent on antibodies to astrocytic AQP4, the role of AQP4-specific T cells for the localization and quality of NMOSD lesions in the CNS is not known. Only recently, we established that thymic B cells express and present AQP4 in the context of MHC class II molecules to purge the naive T cell receptor repertoire of AQP4-specific clones. Here, we exploited this finding to investigate the lesion localization in the CNS of B cell conditional AQP4-deficient (Aqp4^ΔB) mice, which harbor AQP4-specific precursors in their naive T cell repertoire and can be sensitized to mount a strong AQP4(201-220)-specific CD4⁺ T cell response. Sensitization of Aqp4^ΔB mice with AQP4(201-220) was sufficient to induce clinical disease. The spatiotemporal lesion distribution and the glial cell response in AQP4(201-220)-induced experimental autoimmune encephalomyelitis (EAE) was compared to classical MOG(35-55)-induced EAE in Aqp4^ΔB mice. In contrast to MOG-EAE, AQP4(201-220)-induced EAE was characterized by midline lesions in the brain, retinal pathology, and lesions at the grey matter/white matter border zone in the spinal cord. Therefore, we conclude that antigen-specific T cells dictate the localization of NMOSD-lesions in the CNS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"27"},"PeriodicalIF":6.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397547","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":"X-linked ubiquitin-specific peptidase 11 (USP11) increases susceptibility to Cushing's disease in women.","authors":"Tao Zhang, Yanting Liu, Fang Liu, Kaiyu Guo, Runhua Tang, Jingwei Ye, Li Xue, Zhipeng Su, Zhe Bao Wu","doi":"10.1186/s40478-025-01938-9","DOIUrl":"10.1186/s40478-025-01938-9","url":null,"abstract":"<p><p>The incidence of pituitary adrenocorticotropic hormone (ACTH)-secreting PitNETs, commonly known as ACTH PitNETs, is significantly higher in females; however, the underlying causes for this gender disparity remain unclear. In this study, we analyzed the expression of deubiquitinating enzymes in functioning ACTH PitNETs from both male and female subjects using RNA sequencing and identified USP11 as a potential susceptibility factor contributing to the higher prevalence of these PitNETs in females. Further investigation revealed that USP11 expression is markedly elevated in female functioning ACTH PitNETs, with levels significantly higher than those observed in male PitNETs and normal pituitary tissue. Experimental data indicate that USP11 promotes the transcription of proopiomelanocortin (POMC) and the secretion of ACTH. In contrast, knockdown of USP11 leads to a substantial reduction in both POMC transcription and ACTH secretion, as demonstrated in both in vitro and in vivo models. Mechanistically, we found that USP11 facilitates the deubiquitination of the key transcription factor TPIT in functioning ACTH PitNETs, enhancing its protein stability and thereby promoting POMC transcription and ACTH secretion. Additionally, virtual screening identified Lomitapide and Nicergoline as potential inhibitors of USP11, reducing POMC expression and ACTH secretion. Thus, USP11 emerges as a potential therapeutic target, and drugs aimed at inhibiting its function could benefit women with Cushing's disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"22"},"PeriodicalIF":6.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254521","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":"Current molecular understanding of central nervous system schwannomas.","authors":"Takahiro Tsuchiya, Satoru Miyawaki, Yu Teranishi, Kenta Ohara, Yudai Hirano, Shotaro Ogawa, Seiei Torazawa, Yu Sakai, Hiroki Hongo, Hideaki Ono, Nobuhito Saito","doi":"10.1186/s40478-025-01937-w","DOIUrl":"10.1186/s40478-025-01937-w","url":null,"abstract":"<p><strong>Background: </strong>Schwannomas are tumors that originate from myelinating Schwann cells and can occur in cranial, spinal, and peripheral nerves. Although our understanding of the molecular biology underlying schwannomas remains incomplete, numerous studies have identified various molecular findings and biomarkers associated with schwannomas of the central nervous system (CNS). The development of these tumors is primarily linked to mutations in the NF2 gene. Merlin, the protein encoded by NF2, is integral to several signaling pathways, including Ras/Raf/MEK/ERK, PI3K/Akt/mTORC1, Wnt/β-catenin, and the Hippo pathway.</p><p><strong>Main body: </strong>Recent research has also uncovered novel genetic alterations, such as the SH3PXD2A::HTRA1 fusion gene, VGLL-fusions in intraparenchymal CNS schwannomas, and the SOX10 mutation particularly in non-vestibular cranial nerve schwannomas. In addition to genetic alterations, research is also being conducted on gene expression and epigenetic regulation, with a focus on NF2 methylation and post-transcriptional silencing by micro RNA. Furthermore, the advent of advanced techniques like single-cell sequencing and multi-omics analysis has facilitated rapid discoveries related to the tumor microenvironment and tumor heterogeneity in schwannomas.</p><p><strong>Conclusion: </strong>A deeper exploration of these molecular findings could clarify the mechanisms of schwannoma tumorigenesis and progression, ultimately guiding the development of new therapeutic targets. This review offers a comprehensive overview of the current molecular understanding of CNS schwannomas, emphasizing the insights gained from previous research, while addressing existing controversies and outlining future research and treatment perspectives.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"24"},"PeriodicalIF":6.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254518","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}