Acta Neuropathologica最新文献

{"title":"Regulated cell death in neurodegeneration: pathways and therapeutic horizons","authors":"Dietmar Rudolf Thal, Bart De Strooper","doi":"10.1007/s00401-024-02808-9","DOIUrl":"10.1007/s00401-024-02808-9","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau accumulation is cleared by the induced expression of VCP via autophagy","authors":"Hoi-Khoanh Giong,&nbsp;Seung Jae Hyeon,&nbsp;Jae-Geun Lee,&nbsp;Hyun-Ju Cho,&nbsp;Uiyeol Park,&nbsp;Thor D. Stein,&nbsp;Junghee Lee,&nbsp;Kweon Yu,&nbsp;Hoon Ryu,&nbsp;Jeong-Soo Lee","doi":"10.1007/s00401-024-02804-z","DOIUrl":"10.1007/s00401-024-02804-z","url":null,"abstract":"<div><p>Tauopathy, including frontotemporal lobar dementia and Alzheimer’s disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human <i>TAU</i>^P301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where <i>VCP</i> overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer’s disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11422276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306917","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":"TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition","authors":"Pascual Torres,&nbsp;Santiago Rico-Rios,&nbsp;Miriam Ceron-Codorniu,&nbsp;Marta Santacreu-Vilaseca,&nbsp;David Seoane-Miraz,&nbsp;Yahya Jad,&nbsp;Victòria Ayala,&nbsp;Guillermo Mariño,&nbsp;Maria Beltran,&nbsp;Maria P. Miralles,&nbsp;Pol Andrés-Benito,&nbsp;Joaquin Fernandez-Irigoyen,&nbsp;Enrique Santamaria,&nbsp;Carlos López-Otín,&nbsp;Rosa M. Soler,&nbsp;Monica Povedano,&nbsp;Isidro Ferrer,&nbsp;Reinald Pamplona,&nbsp;Matthew J. A. Wood,&nbsp;Miguel A. Varela,&nbsp;Manuel Portero-Otin","doi":"10.1007/s00401-024-02780-4","DOIUrl":"10.1007/s00401-024-02780-4","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including <i>ATG4B</i>, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), <i>Atg4b</i> depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and <i>atg4b</i>^{<i>−/−</i>} mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore <i>ATG4B</i> mRNA in <i>TARDBP</i> knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02780-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275595","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":"Association of in vivo retention of [18f] flortaucipir pet with tau neuropathology in corresponding brain regions","authors":"Tove Freiburghaus,&nbsp;Daria Pawlik,&nbsp;Kevin Oliveira Hauer,&nbsp;Rik Ossenkoppele,&nbsp;Olof Strandberg,&nbsp;Antoine Leuzy,&nbsp;Jonathan Rittmo,&nbsp;Cécilia Tremblay,&nbsp;Geidy E. Serrano,&nbsp;Michael J. Pontecorvo,&nbsp;Thomas G. Beach,&nbsp;Ruben Smith,&nbsp;Oskar Hansson","doi":"10.1007/s00401-024-02801-2","DOIUrl":"10.1007/s00401-024-02801-2","url":null,"abstract":"<div><p>[¹⁸F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer’s disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative <i>post-mortem</i> tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [¹⁸F]flortaucipir PET uptake and quantitative <i>post-mortem</i> tau pathology in corresponding brain regions from the AVID A16 end-of-life study (<i>n</i> = 63). All participants underwent [¹⁸F]flortaucipir PET scans prior to death, followed by a detailed <i>post-mortem</i> neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [¹⁸F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [¹⁸F]flortaucipir specificity and level of detection for tau pathology, correlations between [¹⁸F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [¹⁸F]flortaucipir SUVR and <i>post-mortem</i> tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p &lt; 0.0001 for all). The detection threshold of [¹⁸F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [¹⁸F]flortaucipir SUVRs and <i>post-mortem</i> tau pathology in individuals with possible PART. Further, there was no correlation observed between [¹⁸F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range =  – 0.16–0.12; <i>p</i> = 0.48–0.61) or TDP-43 stage (rho-range =  – 0.10 to  – 0.30; <i>p</i> = 0.18–0.65). In conclusion, our in vivo vs <i>post-mortem</i> study shows that the in vivo [¹⁸F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02801-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245601","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":"Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis","authors":"Mónica Zufiría,&nbsp;Oihane Pikatza-Menoio,&nbsp;Maddi Garciandia-Arcelus,&nbsp;Xabier Bengoetxea,&nbsp;Andrés Jiménez,&nbsp;Amaia Elicegui,&nbsp;María Levchuk,&nbsp;Olatz Arnold-García,&nbsp;Jon Ondaro,&nbsp;Pablo Iruzubieta,&nbsp;Laura Rodríguez-Gómez,&nbsp;Uxoa Fernández-Pelayo,&nbsp;Mikel Muñoz-Oreja,&nbsp;Ana Aiastui,&nbsp;José Manuel García-Verdugo,&nbsp;Vicente Herranz-Pérez,&nbsp;Miren Zulaica,&nbsp;Juan José Poza,&nbsp;Rebeca Ruiz-Onandi,&nbsp;Roberto Fernández-Torrón,&nbsp;Juan Bautista Espinal,&nbsp;Mario Bonilla,&nbsp;Ana Lersundi,&nbsp;Gorka Fernández-Eulate,&nbsp;Javier Riancho,&nbsp;Ainara Vallejo-Illarramendi,&nbsp;Ian James Holt,&nbsp;Amets Sáenz,&nbsp;Edoardo Malfatti,&nbsp;Stéphanie Duguez,&nbsp;Lorea Blázquez,&nbsp;Adolfo López de Munain,&nbsp;Gorka Gerenu,&nbsp;Francisco Gil-Bea,&nbsp;Sonia Alonso-Martín","doi":"10.1007/s00401-024-02794-y","DOIUrl":"10.1007/s00401-024-02794-y","url":null,"abstract":"<div><p>Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as <i>TARDBP</i> (TDP-43) and <i>FUS</i>. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (<i>TBPH</i> or <i>caz</i>) in <i>Drosophila</i> muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by <i>foxo</i> inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02794-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234479","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":"HOXD12 defines an age-related aggressive subtype of oligodendroglioma","authors":"Nicholas Nuechterlein,&nbsp;Sadie Cimino,&nbsp;Allison Shelbourn,&nbsp;Vinny Ha,&nbsp;Sonali Arora,&nbsp;Sharika Rajan,&nbsp;Linda G. Shapiro,&nbsp;Eric C. Holland,&nbsp;Kenneth Aldape,&nbsp;Tresa McGranahan,&nbsp;Mark R. Gilbert,&nbsp;Patrick J. Cimino","doi":"10.1007/s00401-024-02802-1","DOIUrl":"10.1007/s00401-024-02802-1","url":null,"abstract":"<div><p>Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR &lt; 0.01, FDR = 1e−5) and the CGGA (<i>p</i> = 0.03, <i>p</i> &lt; 1e−3). <i>HOXD12</i> gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (<i>p</i> &lt; 1e−6, <i>p</i> &lt; 0.001, <i>p</i> &lt; 1e−3) and with older age and higher WHO grade in Capper et al. (<i>p</i> &lt; 0.002, <i>p</i> = 0.014). In the TCGA, <i>HOXD12</i> gene body hypermethylation and elevated expression were independently prognostic of <i>NOTCH1</i> and <i>PIK3CA</i> mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with <i>HOXD12</i> gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02802-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166235","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":"Autophagy–lysosomal-associated neuronal death in neurodegenerative disease","authors":"Ralph A. Nixon","doi":"10.1007/s00401-024-02799-7","DOIUrl":"10.1007/s00401-024-02799-7","url":null,"abstract":"<div><p>Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal (“phagy”) functions, heightens the neuron’s vulnerability to genetic and environmental factors underlying Alzheimer’s disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy–lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an “inside-out” origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest “<i>intraneuronal</i>” stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02799-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166236","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":"Multiciliated ependymal cells: an update on biology and pathology in the adult brain","authors":"Adam M. R. Groh,&nbsp;Yeji Lori Song,&nbsp;Fiona Tea,&nbsp;Brianna Lu,&nbsp;Stephanie Huynh,&nbsp;Elia Afanasiev,&nbsp;Maxime Bigotte,&nbsp;Marc R. Del Bigio,&nbsp;Jo Jo Anne Stratton","doi":"10.1007/s00401-024-02784-0","DOIUrl":"10.1007/s00401-024-02784-0","url":null,"abstract":"<div><p>Mature multiciliated ependymal cells line the cerebral ventricles where they form a partial barrier between the cerebrospinal fluid (CSF) and brain parenchyma and regulate local CSF microcirculation through coordinated ciliary beating. Although the ependyma is a highly specialized brain interface with barrier, trophic, and perhaps even regenerative capacity, it remains a misfit in the canon of glial neurobiology. We provide an update to seminal reviews in the field by conducting a scoping review of the post-2010 mature multiciliated ependymal cell literature. We delineate how recent findings have either called into question or substantiated classical views of the ependymal cell. Beyond this synthesis, we document the basic methodologies and study characteristics used to describe multiciliated ependymal cells since 1980. Our review serves as a comprehensive resource for future investigations of mature multiciliated ependymal cells.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance","authors":"Lotte Stegat,&nbsp;Alicia Eckhardt,&nbsp;Antonia Gocke,&nbsp;Sina Neyazi,&nbsp;Lara Pohl,&nbsp;Simone Schmid,&nbsp;Matthias Dottermusch,&nbsp;Stephan Frank,&nbsp;Hans Pinnschmidt,&nbsp;Jochen Herms,&nbsp;Markus Glatzel,&nbsp;Matija Snuderl,&nbsp;Leonille Schweizer,&nbsp;Christian Thomas,&nbsp;Julia Neumann,&nbsp;Mario M. Dorostkar,&nbsp;Ulrich Schüller,&nbsp;Annika K. Wefers","doi":"10.1007/s00401-024-02800-3","DOIUrl":"10.1007/s00401-024-02800-3","url":null,"abstract":"<div><p>H3 K27M-altered diffuse midline gliomas (DMGs) are highly malignant tumours that arise in the midline structures of the CNS. Most DMGs carry an H3 K27M-mutation in one of the genes encoding for histone H3. Recent studies suggested that epigenetic subgroups of DMGs can be distinguished based on alterations in the MAPK-signalling pathway, tumour localisation, mutant H3-gene, or overall survival (OS). However, as these parameters were studied individually, it is unclear how they collectively influence survival. Hence, we analysed dependencies between different parameters, to define novel epigenetic, clinically meaningful subgroups of DMGs. We collected a multifaceted cohort of 149 H3 K27M-mutant DMGs, also incorporating data of published cases. DMGs were included in the study if they could be clearly allocated to the spinal cord (<i>n</i> = 31; one patient with an additional sellar tumour), medulla (<i>n</i> = 20), pons (<i>n</i> = 64) or thalamus (<i>n</i> = 33), irrespective of further known characteristics. We then performed global genome-wide DNA methylation profiling and, for a subset, DNA sequencing and survival analyses. Unsupervised hierarchical clustering of DNA methylation data indicated two clusters of DMGs, i.e. subtypes DMG-A and DMG-B. These subtypes differed in mutational spectrum, tumour localisation, age at diagnosis and overall survival. DMG-A was enriched for DMGs with MAPK-mutations<i>,</i> medullary localisation and adult age. 13% of DMG-A had a methylated <i>MGMT</i> promoter. Contrarily, DMG-B was enriched for cases with <i>TP53</i>-mutations, <i>PDGFRA</i>-amplifications, pontine localisation and paediatric patients. In univariate analyses, the features enriched in DMG-B were associated with a poorer survival. However, all significant parameters tested were dependent on the cluster attribution, which had the largest effect on survival: DMG-A had a significantly better survival compared to DMG-B (<i>p</i> &lt; 0.001). Hence, the subtype attribution based on two methylation clusters can be used to predict survival as it integrates different molecular and clinical parameters.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02800-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166234","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":"Novel mutation of SMPX-related scapuloperoneal myopathy and myofibrillar myopathy","authors":"Zhenyu Li,&nbsp;Xujun Chu,&nbsp;Yize Li,&nbsp;Zhiying Xie,&nbsp;Meng Yu,&nbsp;Jianwen Deng,&nbsp;He Lv,&nbsp;Wei Zhang,&nbsp;Zhaoxia Wang,&nbsp;Yun Yuan,&nbsp;Lingchao Meng","doi":"10.1007/s00401-024-02798-8","DOIUrl":"10.1007/s00401-024-02798-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02798-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124415","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}