Acta Neuropathologica最新文献

{"title":"TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects","authors":"Irene García-Toledo,&nbsp;Juan M. Godoy-Corchuelo,&nbsp;Luis C. Fernández-Beltrán,&nbsp;Zeinab Ali,&nbsp;Ariadna Guindo-Arroyo,&nbsp;Irene Jiménez-Coca,&nbsp;Jesús Jiménez-Rodríguez,&nbsp;Karen Javaloyes-García,&nbsp;Marcos Viñuela,&nbsp;Ulises Gómez-Pinedo,&nbsp;Laura Saiz-Aúz,&nbsp;Alberto Rábano,&nbsp;Estela Área-Gómez,&nbsp;Thomas J. Cunningham,&nbsp;Silvia Corrochano","doi":"10.1007/s00401-025-02927-x","DOIUrl":"10.1007/s00401-025-02927-x","url":null,"abstract":"<div><p>TDP-43 is a nuclear protein encoded by the <i>TARDBP</i> gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the <i>Tardbp</i>^{<i>M323K/M323K</i>} knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02927-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Down syndrome and a presenilin 2 variant: dual genetic risk of Alzheimer’s disease","authors":"Jordan Ogg,&nbsp;Nadia Postupna,&nbsp;Laura E. Gibbons,&nbsp;Jeanelle Ariza,&nbsp;Ming Xiao,&nbsp;Luciana M. Fonseca,&nbsp;Suman Jayadev,&nbsp;C. Dirk Keene,&nbsp;Thomas D. Bird,&nbsp;Caitlin S. Latimer","doi":"10.1007/s00401-025-02931-1","DOIUrl":"10.1007/s00401-025-02931-1","url":null,"abstract":"<div><p>Early onset familial Alzheimer’s disease (EOFAD) is rare compared to sporadic AD, but dominant variants in genes involved in amyloid β (Aβ) processing are well-described. One such variant is in the presenilin 2 (<i>PSEN2)</i> gene, N141I, and was first described in a family with Volga German descent. Separately, individuals with Down syndrome (DS) are also at risk for early onset AD, having an extra copy of an amyloid precursor protein gene. While either can drive EOFAD alone, it is extremely rare for both to occur within one individual. Here we describe a unique case of a 48-year-old individual, with both DS and the <i>PSEN2</i> N141I variant. We investigated whether having two high-risk AD variants results in worsened or distinct pathology compared to single variant carriers. Neuropathologic evaluation, quantitative pathology, and spatial proteomic profiling (NanoString Geomx Digital Spatial Profiling) were performed on post-mortem tissue of the index case compared to individuals with DS and N141I variants alone. Analysis in the index case revealed increased total Aβ burden in multiple brain regions compared to the average levels observed in <i>PSEN2</i> carriers and DS cases, but not for hyperphosphorylated tau or neuroinflammatory markers. Index case appeared to have more pronounced Aβ pathological burden than the <i>PSEN2</i> subgroup and was more similar to the DS subgroup in several measurements: the Aβ burden, density of Aβ plaques, fibrillar and dense-core plaques, and the density of ionized calcium binding adaptor molecule 1 (Iba1) labelling in MSTG. As such, it appears that compounded genetic risk for AD was additive for Aβ burden, but not tau or neuroinflammation. This rare case offers new insight into how compounded risk may additively enhance amyloid pathology independently from tau. This underscores the importance of investigating synergistic and additive risk in neurodegenerative disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02931-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare FN1 missense mutations indicate a protective role against Lewy body dementia in APOEε4 homozygous carriers","authors":"Paolo Reho,&nbsp;Anindita Ray,&nbsp;Karri Kaivola,&nbsp;International L. B. D. Genomics Consortium,&nbsp;Badri N. Vardarajan,&nbsp;Haotian Wu,&nbsp;Sonja W. Scholz","doi":"10.1007/s00401-025-02925-z","DOIUrl":"10.1007/s00401-025-02925-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02925-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144918649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation analysis reveals an epigenetic signature distinctive of high-grade oligodendroglioma","authors":"Katharina Johanna Weber,&nbsp;Mareike Dettki,&nbsp;Marco Münzberg,&nbsp;Pia Susann Zeiner,&nbsp;Marie-Thérèse Forster,&nbsp;Eike Steidl,&nbsp;Iris Divé,&nbsp;Patrick Nikolaus Harter,&nbsp;Michael Scherer","doi":"10.1007/s00401-025-02926-y","DOIUrl":"10.1007/s00401-025-02926-y","url":null,"abstract":"<div><p>IDH-mutant gliomas represent a subtype of diffuse gliomas that primarily affect patients in early to mid-adolescence. These tumors are classified into three distinct CNS WHO grades of malignancy. Accurate grading is essential for selecting an appropriate treatment maximizing anti-tumor efficacy while minimizing adverse effects. However, grading of oligodendrogliomas with 1p/19q codeletion currently relies on qualitative tumor characteristics that may be influenced by observer subjectivity, sampling bias, and tumor heterogeneity. This study aimed to explore DNA methylation-based tumor deconvolution into latent methylation components (LMCs) to evaluate their potential as objective grading tools in a cohort of 137 IDH-mutant gliomas. LMCs were analyzed in relation to malignancy markers, cellular composition, and underlying methylation signatures of the chromatin landscape. Glioma subtypes were associated with distinct LMCs. Two LMCs correlated with higher cellular density and advanced epigenetic age as well as with microvascular proliferation, necrosis, and epigenetically defined high-grade astrocytoma. The epigenetic patterns defining high-grade astrocytoma or oligodendroglioma, respectively, were similar. Higher-grade oligodendrogliomas, identified by LMC-based grading, were associated with more copy number alterations. Among patients of an external cohort who died during the assessment period, higher LMC1 proportions were associated with poorer overall survival. Therefore, LMCs hold the potential to support IDH-mutant glioma grading by incorporating objective epigenetic markers.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02926-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGFR alteration is an adverse prognostic factor in IDH-mutant astrocytoma","authors":"Cheyanne C. Slocum,&nbsp;Phuong Nguyen,&nbsp;Meenakshi Vij,&nbsp;Raymund L. Yong,&nbsp;Jorge Samanamud,&nbsp;Satomi Hiya,&nbsp;Carolina Maldonado-Díaz,&nbsp;Melissa Umphlett,&nbsp;Thenzing J. Silva-Hurtado,&nbsp;Kimmo J. Hatanpaa,&nbsp;Mariano S. Viapiano,&nbsp;Matija Snuderl,&nbsp;Kalil G. Abdullah,&nbsp;Samuel K. McBrayer,&nbsp;Dolores Hambardzumyan,&nbsp;Jamie M. Walker,&nbsp;Nadejda M. Tsankova,&nbsp;Timothy E. Richardson","doi":"10.1007/s00401-025-02928-w","DOIUrl":"10.1007/s00401-025-02928-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02928-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144868859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology","authors":"Toru Yamashita,&nbsp;Osamu Yokota,&nbsp;Daiki Ousaka,&nbsp;Hongming Sun,&nbsp;Takashi Haraguchi,&nbsp;Ricardo Satoshi Ota-Elliott,&nbsp;Chika Matsuoka,&nbsp;Tomohito Kawano,&nbsp;Hanae Nakashima-Yasuda,&nbsp;Yusuke Fukui,&nbsp;Yumiko Nakano,&nbsp;Ryuta Morihara,&nbsp;Masato Hasegawa,&nbsp;Yasuyuki Hosono,&nbsp;Seishi Terada,&nbsp;Manabu Takaki,&nbsp;Hiroyuki Ishiura","doi":"10.1007/s00401-025-02899-y","DOIUrl":"10.1007/s00401-025-02899-y","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in <i>DNAJC7</i>, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in <i>DNAJC7</i> expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, <i>DNAJC7</i> knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas <i>DNAJC7</i> overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, <i>dnajc7</i> knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in <i>DNAJC7</i> to familial ALS with TDP-43 pathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02899-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diffuse leptomeningeal glioneuronal tumor (DLGNT): a comprehensive clinical and molecular analysis","authors":"Margit K. Mikkelsen,&nbsp;Xiaoyu Li,&nbsp;Kaiwen Yu,&nbsp;Anthony A. High,&nbsp;Haiyan Tan,&nbsp;Larissa V. Furtado,&nbsp;Nalin Leelatian,&nbsp;Jessica Bell,&nbsp;Julia D. Berry,&nbsp;Daniel R. Boué,&nbsp;Franklin Chien,&nbsp;Scott L. Coven,&nbsp;Michael C. Dewan,&nbsp;Jason Fangusaro,&nbsp;Jessica B. Foster,&nbsp;Lindsey Hoffman,&nbsp;Julia K. Kofler,&nbsp;Trisha Larkin,&nbsp;Margot Lazow,&nbsp;Adriana May,&nbsp;Bret C. Mobley,&nbsp;Dolly Noun,&nbsp;Benjamin Posorske,&nbsp;Jonathan Schwartz,&nbsp;Ivanna Sheila,&nbsp;Susan Spiller,&nbsp;Ryuma Tanaka,&nbsp;Ibrahim Qaddoumi,&nbsp;Christopher L. Tinkle,&nbsp;Junmin Peng,&nbsp;Giles W. Robinson,&nbsp;Daniel C. Moreira,&nbsp;Jason Chiang","doi":"10.1007/s00401-025-02924-0","DOIUrl":"10.1007/s00401-025-02924-0","url":null,"abstract":"<div><p>Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into presentations and therapies to elucidate prognostic factors and therapeutic targets. Histologic, molecular, and clinical data of 30 patients with DLGNT were analyzed. Median age at diagnosis was 7.5 years (range: 0.9–20 years). Disease was localized at diagnosis in 16 patients (53.3%), predominantly in the spinal cord (14/16, 87.5%). <i>KIAA1549</i>::<i>BRAF</i> fusion occurred in 27 (96.4%) of 28 patients. DNA methylation profiling of 23 tumors classified 4 (17.4%) as DLGNT MC-1, 3 (13.0%) as DLGNT MC-2, and 16 (69.6%) as DLGNT, but not to a specific subclass. Median follow-up was 57.5 months. Most patients (90.0%) received adjuvant therapy. Chemotherapy was the first-line adjuvant therapy in 19 patients (70.4%); targeted therapy in 5 patients (18.5%), and radiotherapy in 2 patients (7.4%). Median progression-free survival (PFS) after first chemotherapy, targeted therapy, or radiotherapy was 44 (1–77) months, 18 (4–39) months, and 16.5 (9–23) months, respectively. Five-year PFS was 15.9% ± 8.0, and 5 year overall survival (OS) was 83.3% ± 8.8. Patients older than 9 years at diagnosis (<i>p</i> = 0.002) and those with MC-2 (<i>p</i> = 0.04) had worse 5 year OS. Multi-omic analysis revealed simultaneous activation of multiple signaling pathways, which may serve as potential therapeutic targets. DLGNT remains challenging to treat, with poor outcomes across modalities. Further investigation of treatment, including targeted therapies addressing activated pathways, is needed to improve patient survival.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02924-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression","authors":"Gema Muñoz González,&nbsp;Bert A. ´t Hart,&nbsp;Marianna Bugiani,&nbsp;Jason R. Plemel,&nbsp;Geert J. Schenk,&nbsp;Gijs Kooij,&nbsp;Antonio Luchicchi","doi":"10.1007/s00401-025-02923-1","DOIUrl":"10.1007/s00401-025-02923-1","url":null,"abstract":"<div><p>Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also ‘normal’ appearing tissue in both white and gray matter, referred to as ‘normal-appearing white matter’ and ‘normal-appearing gray matter’, respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these ‘normal-appearing’ CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02923-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U","authors":"Sara Alidadiani,&nbsp;Júlia Faura,&nbsp;Sarah Wynants,&nbsp;Nele Peeters,&nbsp;Marleen Van den Broeck,&nbsp;Linus De Witte,&nbsp;Rafaela Policarpo,&nbsp;Simon Cheung,&nbsp;Cyril Pottier,&nbsp;Nikhil B. Ghayal,&nbsp;Merel O. Mol,&nbsp;Marka van Blitterswijk,&nbsp;Evan Udine,&nbsp;Mariely DeJesus-Hernandez,&nbsp;Matthew Baker,&nbsp;NiCole A. Finch,&nbsp;Yan W. Asmann,&nbsp;Jeroen G. J. van Rooij,&nbsp;Aivi T. Nguyen,&nbsp;R. Ross Reichard,&nbsp;Alissa L. Nana,&nbsp;Oscar L. Lopez,&nbsp;Adam L. Boxer,&nbsp;Howard J. Rosen,&nbsp;Salvatore Spina,&nbsp;Jochen Herms,&nbsp;Keith A. Josephs,&nbsp;Ronald C. Petersen,&nbsp;Robert A. Rissman,&nbsp;Annie Hiniker,&nbsp;Lee-Cyn Ang,&nbsp;Lea T. Grinberg,&nbsp;Glenda M. Halliday,&nbsp;Bradley F. Boeve,&nbsp;Neill R. Graff-Radford,&nbsp;Harro Seelaar,&nbsp;Manuela Neumann,&nbsp;Julia Kofler,&nbsp;Charles L. White III,&nbsp;William W. Seeley,&nbsp;John C. van Swieten,&nbsp;Dennis W. Dickson,&nbsp;Ian R. A. Mackenzie,&nbsp;Wouter De Coster,&nbsp;Rosa Rademakers","doi":"10.1007/s00401-025-02919-x","DOIUrl":"10.1007/s00401-025-02919-x","url":null,"abstract":"<div><p>Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the <i>GLI1</i> transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (<i>MBP</i>), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02919-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: PART and amyloid cascade hypotheses are alive and well (but are not so simple)","authors":"Heiko Braak,&nbsp;Kelly Del Tredici","doi":"10.1007/s00401-025-02921-3","DOIUrl":"10.1007/s00401-025-02921-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02921-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}