Brain最新文献

{"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":"https://doi.org/10.1093/brain/awaf216","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-06-09","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":"Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder","authors":"Marissa J Maroni, Melissa Barton, Katherine Lynch, Ashish R Deshwar, Philip D Campbell, Josephine Millard, Rachel Lee, Annastelle Cohen, Rili Ahmad, Alekh Paranjapye, Víctor Faundes, Gabriela M Repetto, Caoimhe McKenna, Amelle L Shillington, Chanika Phornphutkul, Hanne B Hove, Grazia M S Mancini, Rachel Schot, Tahsin Stefan Barakat, Christopher M Richmond, Julie Lauzon, Ahmed Ibrahim Elsayed Ibrahim, Caroline Nava, Delphine Héron, Minke M A van Aalst, Slavena Atemin, Mila Sleptsova, Iliyana Aleksandrova, Albena Todorova, Debra L Watkins, Mariya A Kozenko, Daniel Natera-de Benito, Carlos Ortez, Berta Estevez-Arias, François Lecoquierre, Kévin Cassinari, Anne-Marie Guerrot, Jonathan Levy, Xenia Latypova, Alain Verloes, A Micheil Innes, Xiao-Ru Yang, Siddharth Banka, Katharina Vill, Maureen Jacob, Michael Kruer, Peter Skidmore, Carolina I Galaz-Montoya, Somayeh Bakhtiari, Jessica L Mester, Michael Granato, Karim-Jean Armache, Gregory Costain, Erica Korb","doi":"10.1093/brain/awaf212","DOIUrl":"https://doi.org/10.1093/brain/awaf212","url":null,"abstract":"Individuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings, and behavioral analysis of zebrafish and multiple mouse models. We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein, and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within down-regulated genes. Lastly using both zebrafish and mouse models, we found behavioral disruptions that include developmental deficits and sex-specific social behavioral changes. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology, and behavior across multiple models and systems.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"10 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260140","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":"Extending the role of neurofilament light in multiple sclerosis beyond measuring irreversible neurodegeneration","authors":"Nick G Cunniffe","doi":"10.1093/brain/awaf224","DOIUrl":"https://doi.org/10.1093/brain/awaf224","url":null,"abstract":"This scientific commentary refers to ‘Markers of axonal injury in blood and tissue triggered by acute and chronic demyelination’ by Abdelhak et al. (https://doi.org/10.1093/brain/awaf144).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"20 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252305","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":"From signal to senescence: IFNγ drives muscle atrophy in myositis","authors":"Werner Stenzel, Hans-Hilmar Goebel, Marie Holzer","doi":"10.1093/brain/awaf220","DOIUrl":"https://doi.org/10.1093/brain/awaf220","url":null,"abstract":"This scientific commentary refers to ‘Interferon-g causes myogenic cell dysfunction and senescence in immune myopathies’ by Hou et al. (https://doi.org/10.1093/brain/awaf153).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"21 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237704","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":"Academia in the throes of faceless bureaucracy","authors":"Jonathan Pansieri, David Menassa, Sandy Figiel, Marco Pisa, Andrew Lockhart, Vito A G Ricigliano, Meral Seferoglu, Serena Borrelli, Vitória Pimentel, Nita Alpin, Natalia Szejko, Sara Samadzadeh, Vinícius Boldrini, Luis Zarco, Edgar Patricio Correa-Díaz, Jonadab Dos Santos Silva, Enrique Gomez Figueroa, Edgar Carnero Contentti, Emine Rabia Koc, Gloria Dalla Costa, Adriana Casallas-Vanegas, Christos Bakirtzis, Sanja Gluscevic, René Carvajal, Abdulkadir Tunç, Lukas Haider","doi":"10.1093/brain/awaf217","DOIUrl":"https://doi.org/10.1093/brain/awaf217","url":null,"abstract":"Pansieri et al. argue that bureaucracy is suffocating research, as an ever increasing administrative burden consumes researchers’ time and diverts focus from discovery to compliance. They highlight ways in which red tape delays progress, wastes funding, and drives researchers out of academia, and call for systemic change.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"83 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237711","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":"Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.","authors":"Kailee S Ward, Christopher P Ptak, Natalya Pashkova, Tiffany Grider, Tabitha A Peterson, Davide Pareyson, Chiara Pisciotta, Paola Saveri, Isabella Moroni, Matilde Laura, Joshua Burns, Manoj P Menezes, Kayla Cornett, Richard Finkel, Bipasha Mukherjee-Clavin, Charlotte J Sumner, Maxwell Greene, Omer Abdul Hamid, David Herrmann, Reza Sadjadi, David Walk, Stephan Züchner, Mary M Reilly, Steven S Scherer, Robert C Piper, Michael E Shy","doi":"10.1093/brain/awaf219","DOIUrl":"10.1093/brain/awaf219","url":null,"abstract":"<p><p>Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity. Twenty-four presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes. Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246304","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":"Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer’s disease","authors":"Shan Jiang, Malavika Srikanth, Rossana Serpe, Shadi Yavari, Pallavi Gaur, Galen Andrew Collins, Rajesh Soni, Vilas Menon, Natura Myeku","doi":"10.1093/brain/awaf222","DOIUrl":"https://doi.org/10.1093/brain/awaf222","url":null,"abstract":"Alzheimer’s disease (AD) is characterized by the accumulation of pathogenic proteins, notably amyloid-beta and hyperphosphorylated tau, which disrupt neuronal function and contribute to cognitive decline. Although proteotoxic stress is well-established in AD, the role of the ubiquitin-proteasome system (UPS) in maintaining neuronal proteostasis, and how it becomes compromised during disease progression remains incompletely understood. Here we integrated multiple approaches to characterize proteasome function, composition, and regulation in post-mortem human AD brain tissue compared to age-matched controls. These included proteasome kinetic assays, affinity purification of intact 26S proteasomes, in-gel activity assays and proteomics. According to Braak staging, we further interrogated bulk RNA-seq and single-nucleus RNA-seq (sn-RNA-seq) datasets spanning the progression of AD pathology. Finally, we examined Nrf1/NFE2L1 binding and subcellular localization to understand the transcriptional regulation of proteasome genes in AD. We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes. This reduction in proteolytic capacity persisted after proteasome purification, implicating intrinsic defects within the proteasome complex. Proteomic profiling of isolated proteasomes revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g., tau, α-synuclein and SQSTM1/p62), suggesting proteasome entrapment in pathological aggregates. Transcriptomic analyses showed progressive downregulation of constitutive proteasome subunit genes in individuals along the Braak stage axis, with downregulation apparent even at the earliest Braak stages, in tissue without overt tau aggregation. Neurons were disproportionately affected, whereas non-neuronal cells did not show substantial differences in proteasome-related gene expression, possibly through immunoproteasome induction. Despite elevated NFE2L1 expression, a key transcription factor normally driving proteasome gene transcription, AD brains exhibited impaired Nrf1 nuclear localization, preventing the expected compensatory upregulation of proteasome components. Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course. Intrinsic alterations in proteasome complexes, coupled with early transcriptional downregulation of proteasome subunits and disrupted Nrf1-mediated regulatory pathways, contribute to a vicious cycle of proteotoxic stress and neuronal vulnerability. Restoring proteasome function and enhancing Nrf1-driven transcriptional responses may represent promising therapeutic strategies to preserve proteostasis and mitigate neurodegeneration in AD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"16 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237705","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":"Collapse of interictal suppressive networks permits seizure spread","authors":"Ghassan S Makhoul, Derek J Doss, Graham W Johnson, C Price Withers, Addison C Cavender, Bruno Hidalgo Monroy Lerma, Anas Reda, Camden E Bibro, Emily Liao, Hakmook Kang, Benoit M Dawant, Shilpa B Reddy, Angela N Crudele, Christos Constantinidis, Shawniqua Williams Roberson, Sarah K Bick, Victoria L Morgan, Dario J Englot","doi":"10.1093/brain/awaf215","DOIUrl":"https://doi.org/10.1093/brain/awaf215","url":null,"abstract":"How do brain networks limit seizure activity? In the Interictal Suppression Hypothesis, we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression. If broad networks appear to be responsible for interictal SOZ suppression, what changes during seizure initiation, spread, and termination? For patients with drug-resistant epilepsy, intracranial monitoring offers a view into the electrographic networks which organize around and in response to the SOZ. In this manuscript, we investigate network dynamics in the peri-ictal periods to assess possible mechanisms of seizure suppression and the consequences of this suppression being overwhelmed. Peri-ictal network dynamics were derived from stereo electroencephalography recordings from 75 patients with drug-resistant epilepsy undergoing pre-surgical evaluation at Vanderbilt University Medical Center. We computed directed connectivity from 5-second windows in the periods between, immediately before, during, and after 668 seizures. We aligned connectivity matrices across seizures and patients, then calculated net connectivity changes from the SOZ, propagative zone, and NIZ. Across all seizure types, we observed two phases: a rapid increase in directed communication towards the SOZ followed by a collapse in network connectivity. During this first phase, SOZs could be distinguished from all other regions (One-Way ANOVA, P-value = 8.32x10-19-2.22x10-7). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (One-Way ANOVA, P-value = 2.58x10-10-1.66x10-2). NIZs appeared to drive increased SOZ connectivity while intra-NIZ connectivity concordantly decreased. Stratifying by seizure subtype, we found that consciousness-impairing seizures decrease inward connectivity from the NIZ earlier than consciousness-sparing seizures (one-way ANOVA, p&amp;lt;0.01 after false discovery correction). Tracking network reorganization against a surrogate for seizure involvement highlighted a possible antagonism between seizure propagation and the NIZ’s ability to maintain high connectivity to the SOZ. Finally, we found that inclusion of peri-ictal connectivity improved SOZ classification accuracy from previous models to a combined area under the curve of 93%. Overall, NIZs appear to actively increase inhibitory signaling towards the SOZ during seizure onset, possibly to thwart seizure activity. While inhibition appears insufficient to prevent seizure onset, the inability to restrict seizure propagation may contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work may: i) facilitate accurate delineation of surgical targets in focal epilepsy, ii) reveal why interictal suppression of SOZs may be insufficient to prevent all seizures, and iii) provide insight into mechanisms of loss of consciousness during certain seizures.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"5 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228455","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":"Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease.","authors":"Sarah McGlasson, Katy Reid, Anna Klingseisen, Bastien Rioux, Samuel Chauvin, Cathrine A Miner, Joe Holley, Deborah Forbes, Bethany Geary, Jeffrey Kimber, Katrina Wood, Candice Roufosse, Colin Smith, David Kavanagh, Jonathan Miner, David P J Hunt","doi":"10.1093/brain/awaf085","DOIUrl":"https://doi.org/10.1093/brain/awaf085","url":null,"abstract":"<p><p>Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an incurable microvascular disease caused by C-terminus truncation of the TREX1 exonuclease. There is a pressing need to understand disease mechanisms and identify therapeutic targets. We evaluated TREX1 sequencing data from 469 229 UK Biobank participants together with RVCL-S-related microvascular clinical and imaging outcomes. We show that mono-allelic truncating mutations in TREX1 require intact nuclease activity in order to cause endothelial disease. Differential proteomics identifies loss of interaction with endoplasmic reticulum insertion proteins such as Guided Entry of Tail-Anchored Proteins Factor 3 as a major consequence of pathogenic TREX1 truncation, and this altered trafficking results in the unregulated presence of enzymatically active TREX1 in the nucleus. In endothelial cells with a patient mutation, mislocalized yet enzymatically active TREX1 causes accumulation of a spectrum of DNA damage. These pathological changes can be rescued by inhibiting exonuclease activity. In summary, our data implicate exonuclease-dependent DNA damage in endothelial cells as a key therapeutic target in the pathogenesis of RVCL-S.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233113","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":"Functional expression of the T-type Cav3.2 calcium channel in female and male human dorsal root ganglion neurons","authors":"Jean Chemin, Vanessa Soubeyre, Stephanie Shiers, Amaury François, Gaëtan Poulen, Nicolas Lonjon, Florence Vachiery-Lahaye, Luc Bauchet, Pierre François Mery, Theodore J Price, Emmanuel Bourinet","doi":"10.1093/brain/awaf214","DOIUrl":"https://doi.org/10.1093/brain/awaf214","url":null,"abstract":"T-type/Cav3 calcium channels are key in neuronal excitability and pain processing with Cav3.2 being the prominent isoform in primary sensory neurons of the dorsal root ganglion (DRG). Cav3.2 pharmacological inhibition or gene silencing induces analgesia in several preclinical models of inflammatory and neuropathic pain. However, the presence of Cav3.2, encoded by the CACNA1H gene, in human DRG neurons remains unresolved. Using RNA in-situ hybridization and electrophysiological recordings, we show that human DRGs express Cav3.2 in a subset of neurons positive for the neurotrophic factor receptor TrkB (NTRK2 gene). The Cav3.2 current exhibits typical biophysical and pharmacological properties, including inhibition by a low concentration of nickel and by Z944, a specific T-type calcium channel blocker in advanced clinical development. Conversely, ABT-639, a T-type calcium channel inhibitor that failed in Phase 2 trials for pain relief, does not inhibit Cav3.2 currents in human DRG neurons. Importantly, Cav3.2 currents are prominent in neurons from female organ donors, supporting the presence of sex differences in pain mechanisms in humans. These findings underscore the potential of continued exploration of Cav3.2 as a therapeutic target for pain treatment and highlight a specific subset of human neurons that likely rely on this channel to modulate their excitability.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228637","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}