Brain最新文献

{"title":"How microlearning is reshaping neurology and neuroscience","authors":"Stefano Sandrone","doi":"10.1093/brain/awaf052","DOIUrl":"https://doi.org/10.1093/brain/awaf052","url":null,"abstract":"Microlearning is changing how we learn, formally and informally, one piece at a time. Stefano Sandrone explores its benefits and limitations, and its impact on the world of neuroscience.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"21 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385424","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":"De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome.","authors":"Kevin T A Booth, Sharayu V Jangam, Martin M C Chui, Kayla Treat, Lorenzo Graziani, Alessia Soldano, Yao Ruan, Jeffrey Wan-Hei Hui, Kerry White, Celanie K Christensen, Ty Lynnes, Shinya Yamamoto, Oguz Kanca, Mandy H Y Tsang, Sally A Lynch, Sureni V Mullegama, Julia Batista, Daniela Iancu, Shelagh K Joss, Sandra Y Y Wong, Christopher C Y Mak, Anna K Y Kwong, Hugo J Bellen, Erin Conboy, Remo Sanges, Anskar Yu-Hung Leung, Michael F Wangler, Brian H Y Chung, Francesco Vetrini","doi":"10.1093/brain/awaf035","DOIUrl":"https://doi.org/10.1093/brain/awaf035","url":null,"abstract":"<p><p>DDX39B is a conserved member of the DEAD-box family of ATP-dependent RNA helicases, critical in mRNA metabolism across eukaryotes. DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, which recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four harboring de novo missense variants in DDX39B, and one with an inherited splicing variant, presenting with variable developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities, dysmorphic features and microcephaly in three patients. 3D molecular modeling predicts these variants would alter protein structure. In vitro studies using overexpression of HA-tagged human DDX39B protein in 293FT cells revealed variants p.(Gly92Asp) and c.433-1G>T impaired interaction with DDX39B and other TREX complex members, while variants p.(Gly37Cys), p.(Ser44Arg), and p.(Arg123Gln) did not affect TREX complex assembly. Blood transcriptomics studies demonstrated significantly elevated aberrant splicing events in individuals carrying the p.(Gly37Cys), p.(Arg123Gln), and c.433-1G>T variant, compared to controls, suggesting a mRNA signature of disrupted mRNA splicing and export. To understand variant effects in vivo, we generated Drosophila transgenic DDX39B-reference and variant flies. Human reference DDX39B when overexpressed ubiquitously led to lethality but the patient variants did not, suggesting that the mutants are loss-of-function alleles. Zebrafish anti-sense morpholino knockdown of DDX39B led to reduced head size and body length consistent with the patient phenotypes, and these effects were mitigated by synthesized mRNA, indicating a loss-of-function effect of DDX39B. Collectively, our human genetic data, coupled with in silico, in vitro, and in vivo data supports that DDX39B is a novel candidate gene in a potential group of disorders called TREX-complex-related neurodevelopmental syndrome.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363624","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":"Reply: Yes, the human brain has around 86 billion neurons.","authors":"Alain Goriely","doi":"10.1093/brain/awaf049","DOIUrl":"https://doi.org/10.1093/brain/awaf049","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363625","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":"Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss","authors":"Axel Chemla, Giuseppe Arena, Ginevra Sacripanti, Kyriaki Barmpa, Alise Zagare, Pierre Garcia, Vyron Gorgogietas, Paul Antony, Jochen Ohnmacht, Alexandre Baron, Jaqueline Jung, Frida Lind-Holm Mogensen, Alessandro Michelucci, Anne-Marie Marzesco, Manuel Buttini, Thorsten Schmidt, Anne Grünewald, Jens C Schwamborn, Rejko Krüger, Cláudia Saraiva","doi":"10.1093/brain/awaf051","DOIUrl":"https://doi.org/10.1093/brain/awaf051","url":null,"abstract":"The complex and heterogeneous nature of Parkinson’s disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients. Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD. Experimental work performed in induced pluripotent stem cells (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. This was accompanied by increased α-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation – located in the calcium-binding domain of the GTPase – disrupted calcium homeostasis. This resulted in the calcium-dependent activation of calpain proteases and the subsequent cleavage of α-synuclein. Knock-in mice expressing p.R285Q Miro1 (the orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated α-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra, accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"47 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258316","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":"Yes, the human brain has around 86 billion neurons.","authors":"Roberto Lent","doi":"10.1093/brain/awaf048","DOIUrl":"https://doi.org/10.1093/brain/awaf048","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363626","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":"Correction to: Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison.","authors":"","doi":"10.1093/brain/awaf034","DOIUrl":"https://doi.org/10.1093/brain/awaf034","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254828","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":"Overstating harms can have consequences.","authors":"Richard S Bedlack","doi":"10.1093/brain/awaf046","DOIUrl":"https://doi.org/10.1093/brain/awaf046","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254830","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":"Converging cross-modal evidence for a phylogenetic age effect in neurodegenerative susceptibility.","authors":"Laura Iris Van Hove, François-Laurent De Winter, Qi Zhu, Gert Cypers, Wim Vanduffel, Beatrice de Gelder, Mathieu Vandenbulcke, Jan Van den Stock","doi":"10.1093/brain/awaf050","DOIUrl":"https://doi.org/10.1093/brain/awaf050","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254807","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":"Reply: Overstating harms can have consequences.","authors":"Michael Benatar, Christopher McDermott, Martin R Turner, Ruben P A van Eijk","doi":"10.1093/brain/awaf047","DOIUrl":"https://doi.org/10.1093/brain/awaf047","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254849","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":"The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset","authors":"Haiyan Liu, Thomas W Marsh, Xinyu Shi, Alan E Renton, Kevin M Bowling, Ellen Ziegemeier, Guoqiao Wang, Yuchen Cao, Alisha Aristel, Jessie Li, Alexa Dickson, Richard J Perrin, Alison M Goate, Victoria Fernández, Gregory S Day, Michelle Doering, Alisha Daniels, Brian A Gordon, Tammie L S Benzinger, Jason Hassenstab, Laura Ibanez, Charlene Supnet-Bell, Chengjie Xiong, Ricardo Allegri, Sarah B Berman, Nick C Fox, Natalie Ryan, Edward D Huey, Jonathan Vöglein, James M Noble, Jee Hoon Roh, Mathias Jucker, Christoph Laske, Takeshi Ikeuchi, Raquel Sanchez-Valle, Peter R Schofield, Patricio Chrem Mendez, Jasmeer P Chhatwal, Martin Farlow, Jae-Hong Lee, Allan I Levey, Johannes Levin, Francisco Lopera, Ralph Martins, Yoshiki Niimi, Pedro Rosa-Neto, John C Morris, Randall J Bateman, Celeste M Karch, Carlos Cruchaga, Eric McDade, Jorge J Llibre-Guerra","doi":"10.1093/brain/awaf038","DOIUrl":"https://doi.org/10.1093/brain/awaf038","url":null,"abstract":"We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer's disease (ADAD). A total of 550 variants in the APP, PSEN1, and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on ACMG-AMP criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature, and public databases. Symptomatic age at onset (AAO) data was estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity, and AAO. Importantly, 226 variants meet eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrate the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study (DIAN-OBS). This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"41 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125280","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}