Brain最新文献

{"title":"Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal.","authors":"Valentina Lacovich,Stanislav Stejskal,Kristina Locker Kovačovicova,David Potěšil,Vaclav Pustka,Dragana Vukić,Katerina Texlova,Pavla Linhartova,Janka Melicherova,Ketty Sinigaglia,Daniel Havas,Liam P Keegan,Mary A O'Connell","doi":"10.1093/brain/awaf315","DOIUrl":"https://doi.org/10.1093/brain/awaf315","url":null,"abstract":"Mutations in the human ADAR gene encoding adenosine deaminase acting on RNA 1 (ADAR1) cause Aicardi-Goutières syndrome 6 (AGS6); a severe auto-inflammatory encephalopathy with aberrant interferon (IFN) induction. AdarΔ2-13 null mutant mouse embryos lacking ADAR1 protein die with high levels of IFN-stimulated gene (ISG) transcripts. In Adar Mavs double mutants also lacking the Mitochondrial antiviral signaling (MAVS) adaptor, the aberrant IFN induction is prevented. Live pups are born and survive for two weeks, allowing ADAR1 function to be investigated. We have shown that early death of Adar Mavs mutants is rescued by the deletion of the Eif2ak2 gene encoding the antiviral dsRNA sensor protein kinase R (PKR). Here, we focused on characterizing the brain defects in Adar Mavs mutants and their dependencies on PKR. Mouse brains were collected on postnatal days 8 and 14, analysed by mass spectrometry, immunohistochemistry and RT-qPCR. The proteomic analyses showed upregulation of ISG-encoded proteins in the Adar Mavs double mutant and the morphological analyses confirmed the aberrant microgliosis in brains. Both are prevented in Adar Mavs Eif2ak2 triple mutants, indicating the key role of aberrant PKR activation; PKR expression is also increased by IFN signaling. Altered expression levels of transcripts encoding differentially expressed proteins and of ADAR-edited transcripts were confirmed by RT-qPCR. Analysis of the expression levels of transcripts in the brains of mutants expressing a catalytically-inactive ADAR E861A protein, revealed that the levels of some but not all altered transcripts are restored. A further group of proteins, downregulated in Adar Mavs are not rescued by removing PKR and may result from effects of loss of the widespread ADAR1 RNA editing known to occur in brain transcripts. This group includes several motor proteins, some of which have been reported to be encoded by ADAR-edited transcripts. In this study we show Adar Mavs double mutants exhibit an aberrant IFN response in the brain likely due to reactive microglia and astrocytes. Microgliosis, which is rescued in the triple mutant, is mostly dependent on aberrant PKR activation and is partially RNA-editing dependent.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"24 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008865","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":"Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity.","authors":"Olga Carletta,Camilla Perfetto,Olivia M Rifai,Francesca Manganelli,Fergal M Waldron,Tom Maniatis,Jenna M Gregory,Valeria Gerbino","doi":"10.1093/brain/awaf324","DOIUrl":"https://doi.org/10.1093/brain/awaf324","url":null,"abstract":"Innate immune signaling pathways are hyperactivated in the central nervous system (CNS) of patients with Amyotrophic Lateral Sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1, and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial. Here, we systematically profile Type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n=18), genetic ALS caused by (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n=11), and (ii) a SOD1 mutation (SOD1-ALS; n=5), alongside age- and sex-matched individuals who died of a non-neurological cause (n=12). Using this deeply phenotyped cohort we have implemented targeted transcriptomic analysis and immunohistochemistry to interrogate the nature and extent of the activation of the Type-I IFN response in patients. We determined disease and genotype specific IFN signatures that correlate with clinical phenotype. Correlation analysis linked six ISGs with aggressive disease progression, as indicated by negative correlation with age at death in ALS patients. Notably, significant upregulation of ISGs was observed in C9-ALS patients, with higher ISG expression correlating with shorter disease duration. Noting that our genotype and disease specific signatures correlated with metrics of disease progression, we explored the therapeutic potential of targeting this pathway in a mouse model of ALS. Treatment with an IFN pathway inhibitor reduced IFN response markers, delayed disease progression, including motor decline, and extended survival in ALS mice. We conclude that upregulation of gene expression in the Type-I IFN pathway represents a key pathological feature of ALS and that inhibiting this pathway may provide a promising therapeutic approach for treating ALS.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995766","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":"Compensatory roles of STT3A and ALG5 in glucose metabolism of aged macaque hippocampus.","authors":"Gao-Hong Zhu,Rui He,Zhi-Yu Yang,Ting-Ting Wang,Shi-Ci Yang,Ya-Xi Jiang,Jie Li,Yao-Hui Zhang,Fu-Xing Zhao,Yun Deng,Ting-Ting Pan,Xue-Dan Liu,Bao-Ci Shan,Xiang-Qing Zhu,Stefan H Bossmann,Xing-Hua Pan,Ting-Hua Wang","doi":"10.1093/brain/awaf282","DOIUrl":"https://doi.org/10.1093/brain/awaf282","url":null,"abstract":"The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming. Mechanistically, STT3A/ALG5 silencing in aged rats reduced insulin receptor/AKT1/AS160 phosphorylation, impairing GLUT4 membrane trafficking, while enhancing GLUT3 glycosylation and neuronal glucose uptake. This dual regulation preserved synaptic integrity and spatial memory retrieval despite reduced hippocampal FDG metabolism. Behavioral assays further demonstrated STT3A knockdown-induced motor coordination improvements through GLUT3-mediated metabolic rebalancing. Our findings establish STT3A-ALG5 as a glycosylation checkpoint that sustains HC energy homeostasis via GLUT4-to-GLUT3 substrate switching, positioning 18F-FDG PET as a dynamic biomarker for monitoring HC aging and these glycosyltransferases as therapeutic targets against cognitive decline.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"53 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995764","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":"A large cohort study of prenatal exome sequencing redefines diagnosis in fetal corpus callosum anomalies.","authors":"Delphine Héron,Anna Gerasimenko,Lisa Frugère,Jade Ducourneau,Capucine Rossi,Caroline Nava,Jean-Madeleine de Sainte-Agathe,Cyril Mignot,Daphné Lehalle,Sarah Grotto,Laila El-Khattabi,Toan Nguyen,Catherine Garel,Eleonore Blondiaux,Mathieu Milh,Béatrice Desnous,Nadine Girard,Vincent des Portes,Laurent Guibaud,Isabelle Sabatier,Olivier Patat,Sophie Julia,Alexandra Benachi,Alexandre Vivanti,Olivier Picone,Agnès Guet,Mathilde Nizon,Marie Vincent,Solène Conrad,Claudine Le Vaillant,Thierry Billette de Villemeur,Sébastien Moutton,Vassilis Tsatsaris,Lucie Guilbaud,Jean-Marie Jouannic,Stéphanie Valence,Boris Keren,Solveig Heide","doi":"10.1093/brain/awaf311","DOIUrl":"https://doi.org/10.1093/brain/awaf311","url":null,"abstract":"Anomalies of the corpus callosum (AnCC) are congenital malformations associated with highly variable neurodevelopmental outcomes. We performed prenatal Exome Sequencing (pES) on a cohort of 352 fetuses diagnosed with AnCC, analyzing the diagnostic yield, the implicated genes based on the type of anomaly (partial or complete agenesis, short corpus callosum, or callosal dysgenesis) and assessing the impact on pregnancy outcomes. The overall diagnostic yield of pES was 23%, with pathogenic or likely pathogenic variants identified in 49 different genes, most of which linked to intellectual developmental disorders. The highest diagnostic yield (46%) was observed in fetuses with callosal dysgenesis. Notably, in cases of corpus callosum agenesis, variants in the DCC gene were the most frequently identified etiology (3.2%, n=9), associated with a favorable neurodevelopmental outcome. All couples with a fetal DCC variant decided to continue the pregnancy to term. In contrast, 73% of couples with other genetic diagnoses chose pregnancy termination, compared to 17% in cases without a genetic diagnosis. pES provides essential prognosis information that supports prenatal decision-making and care. The identification of genes associated with favorable outcomes, along with the integration of pES into prenatal diagnosis, enhances informed decision-making for parents and improves the clinical management of AnCC.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"27 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962743","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":"Neurosyphilis","authors":"Christina M Marra","doi":"10.1093/brain/awaf329","DOIUrl":"https://doi.org/10.1093/brain/awaf329","url":null,"abstract":"The incidence of syphilis has increased world-wide over the last ∼25 years, and this increase has been accompanied by a resurgence of neurosyphilis. This review sets the stage for understanding neurosyphilis by briefly summarizing the clinical and laboratory findings in uncomplicated syphilis. It then addresses the epidemiology, clinical manifestations, and treatment of neurosyphilis beginning with information from the pre-penicillin era and extending to modern studies. Ocular and otosyphilis are included as their treatment is the same as for neurosyphilis. Importantly, the review focuses on areas of uncertainty and controversy, including insights into pathogenesis, new diagnostic tests, the best way to identify individuals at risk for neurosyphilis, and the justification for identifying and treating asymptomatic neurosyphilis in selected situations. The incidence of syphilis has increased worldwide over the last 25 years, and this increase has been accompanied by a resurgence of neurosyphilis. Christina Marra reviews the epidemiology, clinical manifestations, and treatment of neurosyphilis, highlighting areas of uncertainty and controversy.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"35 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002912","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":"Aberrant striatal firing mediates impulsive decision-making in a mouse model of Parkinson's disease.","authors":"Xiaowen Zhuang,Julia Lemak,Sadhana Sridhar,Alexandra B Nelson","doi":"10.1093/brain/awaf312","DOIUrl":"https://doi.org/10.1093/brain/awaf312","url":null,"abstract":"Parkinson's disease (PD) is characterized by progressive neurodegeneration, which is associated with motor and non-motor symptoms. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), characterized by pathological gambling, hypersexuality, and/or compulsive shopping. Approximately 14-40% of all medicated PD patients suffer from ICD. Despite the high prevalence of ICD in medicated PD patients, we know little of its mechanisms, and the main therapeutic strategy is reducing or eliminating dopamine agonist medication. Human imaging studies suggest that the input nucleus of the basal ganglia, the striatum, may be a critical site of circuit dysfunction in ICD. To explore the cellular and circuit mechanisms of ICD, we developed a mouse model in which we administered the dopamine D2/3 agonist pramipexole to parkinsonian and healthy control mice. ICD-like behavior was assessed using a delay discounting task. Delay discounting is a normal cognitive phenomenon, in which the value of a reward decreases according to the time needed to wait for it. Impulsivity is measured as the preference for immediate (small) over delayed (large) rewards. We combined this mouse model with chemogenetics and in vivo optically-identified single-unit recordings to examine how dopamine agonists act on vulnerable striatal circuitry to mediate impulsive decision-making. We found that in parkinsonian mice, therapeutic doses of dopamine D2/3R or D1R agonists drove more pronounced delay discounting, reminiscent of what has been reported in PD/ICD patients on medication. In contrast, healthy mice did not become more impulsive when given the same dose of dopamine agonist. The clinically relevant dopamine D2/3R agonist pramipexole induced marked bidirectional changes in the firing of striatal direct and indirect pathway neurons in parkinsonian mice. Chronic pramipexole treatment potentiated these changes in striatal physiology and decision-making behavior. Furthermore, chemogenetic excitation of direct pathway striatal neurons or inhibition of indirect pathway neurons induced impulsive decision making in the absence of dopamine agonists. These findings indicate that abnormal striatal activity plays a causal role in mediating ICD-like behaviors. Together, they provide a robust mouse model and insights into ICD pathophysiology.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"24 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960168","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":"Quantitative susceptibility mapping reveals differences between subtypes of Lewy body dementia.","authors":"Rohan Bhome,George E C Thomas,Naomi Hannaway,Ivelina Dobreva,Angeliki Zarkali,Karin Shmueli,James H Cole,Rimona S Weil","doi":"10.1093/brain/awaf325","DOIUrl":"https://doi.org/10.1093/brain/awaf325","url":null,"abstract":"Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are subtypes of Lewy body dementia, and are considered two ends of a disease spectrum. However, conventional MRI neuroimaging, mainly focussed on grey matter volume and thickness, has failed to establish whether underlying processes differ between them. Understanding these differences could enable targeted and subtype-specific treatments to be developed. We applied quantitative susceptibility mapping (QSM), an advanced neuroimaging technique sensitive to tissue iron, to examine differences in tissue composition between these Lewy body dementia subtypes. We performed both voxel-wise and region of interest analyses to compare QSM values in 66 people with Lewy body dementia (45 DLB; 21 PDD); 86 people with Parkinson's disease with normal cognition (PD-NC) and 37 healthy controls. We also assessed relationships between QSM values and measures of both cognitive performance and overall disease severity in people with Lewy body dementia. We found that people with Lewy body dementia had higher QSM values in widespread brain regions, compared with cognitively-normal people with PD; and that people with PDD had higher QSM values across many brain regions, compared with people with DLB. Further, we showed a positive relationship between QSM values and overall disease severity, measured using the Movement Disorders Society Unified Parkinson's disease Rating Scale in people with Lewy body dementia, in right thalamus, left pallidum, bilateral substantia nigra, bilateral middle frontal, temporal and lateral occipital lobes, right precentral and superior frontal cortices. In a region of interest analysis, we showed that people with PDD had higher QSM values than cognitively-normal people with PD and controls in the substantia nigra pars reticulata. Our findings indicate neurobiological differences between subtypes of Lewy body dementia, that can be detected by exploiting QSM's sensitivity to tissue composition. Based on this, DLB and PDD could be considered as distinct conditions in the clinic and in clinical trials, and may respond to different treatments. Our finding that QSM values relate to real world measures of overall disease severity in Lewy body dementia indicates its potential as an imaging biomarker for clinical trials of Lewy body dementia interventions.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"38 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960306","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":"Expanding the phenotype of SORD mutation.","authors":"Roxane Pruvost, Arnaud Bruneel, Nicolas Dochez, Grégory Kuchcinski, Vianney Poinsignon, Céline Tard","doi":"10.1093/brain/awaf216","DOIUrl":"10.1093/brain/awaf216","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e79-e80"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246305","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":"Activated αβ T and reduced mucosa-associated invariant T cells in LGI1- and CASPR2-encephalitis.","authors":"Daniela Esser, Louisa Müller-Miny, Michael Heming, Manuela Paunovic, Martijn van Duijn, Ligia Abrante Cabrera, Katharina M Mair, Christine Strippel, Saskia Räuber, Justina Dargvainiene, Stjepana Kovac, Catharina C Gross, Nina Fransen, Robin van Steenhoven, Péter Körtvélyessy, Werner Stenzel, Romana Höftberger, Eric Bindels, Christian G Bien, Heinz Wiendl, Sven G Meuth, Jan Bauer, Nico Melzer, Maarten J Titulaer, Frank Leypoldt, Gerd Meyer Zu Hörste","doi":"10.1093/brain/awaf096","DOIUrl":"10.1093/brain/awaf096","url":null,"abstract":"<p><p>Anti-leucine-rich glioma inactivated-1 (LGI1) and anti-contactin-associated-protein-2 (CASPR2) autoimmune encephalitis (AIE) are common and characterized by pathogenic antibodies targeting neuronal autoantigens. However, the drivers of the antibody-secreting cells and involvement of T cells remain unresolved. We performed single-cell RNA sequencing of fresh CSF and parallel blood samples of 15 patients with LGI1-AIE (n = 9) and CASPR2-AIE (n = 6) compared with control patients [multiple sclerosis (n = 15) and idiopathic intracranial hypertension (n = 18)]. We validated our observations in independent cohorts using flow cytometry of CSF and blood. We confirmed autoantibody specificity using recombinant human monoclonal antibodies. In comparison to idiopathic intracranial hypertension and multiple sclerosis controls, we observed clonal CSF-specific antibody-secreting cell expansion in LGI1/CASPR2-AIE despite mostly normal CSF findings. Antibody-secreting cells were dominantly plasmablasts and transcribed IgG4 and IgG1/2 heavy chains. Expanded clones showed signs of affinity maturation and bound the respective neuronal autoantigen. Within CD4 and CD8 T-cell clusters, CD4 and CD8 central memory T cells were activated, clonally restricted and expanded. T-cell clones were often shared between CSF and blood. We also observed a shift of natural killer cells and loss of mucosa-associated invariant T (MAIT) cells in the CSF of LGI1-AIE and the blood of LGI1- and CASPR2-AIE compared with idiopathic intracranial hypertension and multiple sclerosis controls. MAIT-like T cells were detected in autopsied brains of LGI1- and CASPR2-AIE patients, and mice lacking MAIT cells displayed an increased antibody seroconversion and higher titres following active LGI1/CASPR2 immunization. Our data: (i) confirm the intrathecal antigen-specific plasma cell expansion in LGI1- and CASPR2-AIE in a large cohort of untreated AIE patients; (ii) suggest that activated and expanded central memory CD4 and CD8 T cells in the CSF participate in disease pathogenesis; and (iii) implicate invariant T-cell receptor-expressing lymphocytes in the brain, CSF and blood in disease pathogenesis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3170-3183"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647114","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":"Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.","authors":"Fahri Küçükali, Elizabeth Hill, Tijs Watzeels, Holger Hummerich, Tracy Campbell, Lee Darwent, Steven Collins, Christiane Stehmann, Gabor G Kovacs, Michael D Geschwind, Karl Frontzek, Herbert Budka, Ellen Gelpi, Adriano Aguzzi, Sven J van der Lee, Cornelia M van Duijn, Pawel P Liberski, Miguel Calero, Pascual Sanchez-Juan, Elodie Bouaziz-Amar, Jean-Louis Laplanche, Stéphane Haïk, Jean-Phillipe Brandel, Angela Mammana, Sabina Capellari, Anna Poleggi, Anna Ladogana, Dorina Tiple, Saima Zafar, Stephanie Booth, Gerard H Jansen, Aušrinė Areškevičiūtė, Eva Løbner Lund, Katie Glisic, Piero Parchi, Peter Hermann, Inga Zerr, Jiri Safar, Pierluigi Gambetti, Brian S Appleby, John Collinge, Kristel Sleegers, Simon Mead","doi":"10.1093/brain/awaf032","DOIUrl":"10.1093/brain/awaf032","url":null,"abstract":"<p><p>Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline to the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself, as well as beyond the previously highlighted sCJD risk loci, through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3350-3363"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045021","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}