Brain最新文献

{"title":"Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.","authors":"Baptiste Ropert, Sylvie Bannwarth, Emmanuelle C Genin, Loan Vaillant-Beuchot, Sandra Lacas-Gervais, Blandine Madji Hounoum, Aurore Bernardin, Nhu Dinh, Alessandra Mauri-Crouzet, Marc-Alexandre D'Elia, Gaelle Augé, Françoise Lespinasse, Audrey Di Giorgio, Willian Meira, Nathalie Bonnefoy, Laurent Monassier, Manuel Schiff, Laila Sago, Devrim Kilinc, Frédéric Brau, Virginie Redeker, Delphine Bohl, Déborah Tribouillard-Tanvier, Vincent Procaccio, Stéphane Azoulay, Jean-Ehrland Ricci, Agnès Delahodde, Véronique Paquis-Flucklinger","doi":"10.1093/brain/awae348","DOIUrl":"10.1093/brain/awae348","url":null,"abstract":"<p><p>The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from two repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ induced pluripotent stem cell-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1665-1679"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543592","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":"Single-nucleus transcriptomics reveals disease- and pathology-specific signatures in α-synucleinopathies.","authors":"Gonzalo S Nido, Martina Castelli, Sepideh Mostafavi, Anna Rubiolo, Omnia Shadad, Guido Alves, Ole-Bjørn Tysnes, Irene H Flønes, Christian Dölle, Charalampos Tzoulis","doi":"10.1093/brain/awae355","DOIUrl":"10.1093/brain/awae355","url":null,"abstract":"<p><p>α-Synucleinopathies are progressive neurodegenerative disorders characterized by intracellular aggregation of α-synuclein, but their molecular pathogenesis remains unknown. Here, we explore cell-specific changes in gene expression across different α-synucleinopathies. We perform single-nucleus RNA sequencing on nearly 300 000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinson's disease (PD, n = 20), Parkinson's disease caused by LRRK2 mutations (LRRK2-PD, n = 7), multiple system atrophy (n = 6) and healthy controls (n = 13). Idiopathic PD and LRRK2-PD exhibit a largely overlapping cell type-specific signature, which is distinct from that of multiple system atrophy and includes an overall decrease of the transcriptional output in neurons. Notably, most of the differential expression signal in idiopathic PD and LRRK2-PD is concentrated in a specific deep cortical neuronal subtype expressing adrenoceptor alpha 2A. Although most differentially expressed genes are highly cell type and disease specific, PDE10A is found to be downregulated consistently in most cortical neurons and across all three diseases. Finally, exploiting the variable presence and/or severity of α-synuclein pathology in LRRK2-PD and idiopathic PD, we identify cell type-specific signatures associated with α-synuclein pathology, including a neuronal upregulation of SNCA itself, encoding α-synuclein. Our findings provide new insights into the cell-specific transcriptional landscape of the α-synucleinopathy spectrum.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1588-1603"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12073976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638361","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":"Responses to 'On the responsibilities of intellectuals and the rise of bullshit jobs in universities'.","authors":"Masud Husain","doi":"10.1093/brain/awaf141","DOIUrl":"https://doi.org/10.1093/brain/awaf141","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"148 5","pages":"e48-e49"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976519","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":"Natural history of Becker muscular dystrophy: DMD gene mutations predict clinical severity.","authors":"Domenico Gorgoglione, Daniele Sabbatini, Pietro Riguzzi, Giuliana Capece, Marika Pane, Serenella Servidei, Marta Briganti, Cristina Sancricca, Fabio Bruschi, Anna Ardissone, Riccardo Masson, Annamaria Gallone, Lorenzo Maggi, Esther Picillo, Luisa Politano, Angela Petrosino, Sara Vianello, Martina Penzo, Matteo Villa, Maria Sframeli, Cosimo Allegra, Andrea Barp, Alessandra Di Bari, Francesca Salmin, Emilio Albamonte, Giovanni Colacicco, Chiara Panicucci, Monica Traverso, Concetta Palermo, Alberto Lerario, Daniele Velardo, Maria G D'Angelo, Angela Berardinelli, Alice Gardani, Roberta Nicotra, Stefano Parravicini, Gabriele Siciliano, Giulia Ricci, Francesca Torri, Giulio Gadaleta, Guido Urbano, Enrica Rolle, Federica Ricci, Adele D'Amico, Michela Catteruccia, Antonella Pini, Melania Giannotta, Roberta Battini, Gemma Marinella, Stefano C Previtali, Alberto A Zambon, Alessandra Ferlini, Fernanda Fortunato, Francesca Magri, Tiziana E Mongini, Valeria A Sansone, Claudio Bruno, Sonia Messina, Vincenzo Nigro, Isabella Moroni, Eugenio Mercuri, Luca Bello, Elena Pegoraro","doi":"10.1093/brain/awae358","DOIUrl":"10.1093/brain/awae358","url":null,"abstract":"<p><p>Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease attributable to mutations in DMD, leading to a deficient and less functional dystrophin, mainly in skeletal and cardiac muscle. Understanding the natural history of BMD is crucial for optimizing patient care and developing targeted treatments. Retrospective data were collected from 943 patients diagnosed with BMD based on a combination of clinical, biochemical and genetic criteria followed by 17 Italian neuromuscular centres. Patients' demographics, main signs and symptoms at BMD onset, neuropsychiatric comorbidities, age at loss of ambulation, cardiac left ventricular ejection fraction, pulmonary forced vital capacity and DMD mutations were collected. Disease milestones were analysed in specific DMD mutational groups. The median age at the last assessment was 26.0 (16.6-41.9) years, with a median age at diagnosis of 7.5 (4.0-14.0) years. In 55% of patients, the diagnosis was prompted by the incidental finding of hyperCKaemia. At the last assessment, 13.5% of patients had lost the ability to walk at a median age estimated by Kaplan-Meier analysis of 69 years. Thirty per cent of patients exhibited left ventricular impairment and 2.7% respiratory involvement. Ten per cent of patients carried out-of-frame mutations, 4% nonsense mutations and 86% in-frame deletions/duplications. The subset of in-frame deletions was classified further based on the specific mutations. Patients carrying del45-49 compared with del45-47 were associated with an earlier loss of ambulation (P = 1 × 10-4), whereas patients with del45-55 (P = 0.005), del48 (P = 0.02) and del48-49 (P = 0.02) were correlated with a later loss of ambulation compared with del45-47. Both del45-55 (P = 0.002) and del48 (P = 0.003) were significantly associated with decreased odds of developing a pathological left ventricular ejection fraction compared with del45-47. Our results contribute to a better understanding of the natural history of BMD and capture precious data in the era of emerging therapies. The knowledge of the specific DMD mutation might help to define a prognosis in a subset of BMD patients and will serve as a model for the design of future therapies.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1695-1706"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581297","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":"10.1093/brain/awaf050","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e34-e36"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","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":"Nuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination.","authors":"Bing Han, Ming-Yue Bao, Qing-Qing Sun, Rui-Ning Wang, Xin Deng, Kun Xing, Feng-Lin Yu, Yan Zhang, Yue-Bo Li, Xiu-Qing Li, Na-Nan Chai, Gai-Xin Ma, Ya-Na Yang, Meng-Yuan Tian, Qian Zhang, Xing Li, Yuan Zhang","doi":"10.1093/brain/awae378","DOIUrl":"10.1093/brain/awae378","url":null,"abstract":"<p><p>Myelin injury occurs in brain ageing and in several neurological diseases. Failure of spontaneous remyelination is attributable to insufficient differentiation of oligodendrocyte precursor cells (OPCs) into mature myelin-forming oligodendrocytes in CNS demyelinated lesions. Emerging evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) is the master gatekeeper of CNS injury and repair and plays an important regulatory role in various neurodegenerative diseases. Although studies demonstrate positive effects of PPARγ in oligodendrocyte ontogeny in vitro, the cell-intrinsic role of PPARγ and the molecular mechanisms involved in the processes of OPC development and CNS remyelination in vivo are poorly understood. Here, we identify PPARγ as an enriched transcription factor in the dysfunctional OPCs accumulated in CNS demyelinated lesions. Its expression increases during OPC differentiation and myelination and is closely related to the process of CNS demyelination/remyelination. Administration of pharmacological agonists of PPARγ not only promotes OPC differentiation and CNS myelination, but also causes a significant increase in remyelination in both cuprizone- and lysophosphatidylcholine-induced demyelination models. In contrast, the attenuation of PPARγ function, either through the specific knockout of PPARγ in oligodendrocytes in vivo or through its inhibition in vitro, leads to decreased OPC maturation, hindered myelin generation and reduced therapeutic efficacy of PPARγ agonists. At a mechanistic level, PPARγ induces myelin repair by directly targeting glycoprotein non-metastatic melanoma protein B (GPNMB), a novel regulator that drives OPCs to differentiate into oligodendrocytes, promotes myelinogenesis in the developing CNS of postnatal mice and enhances remyelination in mice with lysophosphatidylcholine-induced demyelination. In conclusion, our evidence reveals that PPARγ is a positive regulator of endogenous OPC differentiation and CNS myelination/remyelination and suggests that PPARγ and/or its downstream sensor (GPNMB) might be a candidate pharmacological target for regenerative therapy in the CNS.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1801-1816"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930694","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":"Overcoming the dopamine-centric model of impulse control disorders in Parkinson’s disease: the role of 5-HT","authors":"Roberto Cilia, Valtteri Kaasinen","doi":"10.1093/brain/awaf145","DOIUrl":"https://doi.org/10.1093/brain/awaf145","url":null,"abstract":"This scientific commentary refers to ‘Serotonergic dysfunction in patients with impulse control disorders in Parkinson’s disease’ by Prange et al. (https://doi.org/10.1093/brain/awaf087).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"57 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940147","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":"Against the moral hemiplegia of the intellectual class.","authors":"José Alberto González Cáceres","doi":"10.1093/brain/awaf138","DOIUrl":"https://doi.org/10.1093/brain/awaf138","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"29 1","pages":"e41-e42"},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945557","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":"10.1093/brain/awaf048","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e37-e38"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","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":"Mental health disorders before, during and after the COVID-19 pandemic: a nationwide study.","authors":"Clara S Grønkjær, Rune H B Christensen, Daniel Kondziella, Michael E Benros","doi":"10.1093/brain/awae360","DOIUrl":"10.1093/brain/awae360","url":null,"abstract":"<p><p>The coronavirus disease 2019 (COVID-19) pandemic and lockdowns prompted a major concern for mental health effects. Comprehensive nationwide studies are lacking on the indirect effect of the COVID-19 pandemic on the mental health of the population. We aimed to determine whether the COVID-19 pandemic and lockdowns affected mental health service usage, suicide attempts and suicides. This comprehensive nationwide register-linked study followed all individuals in Denmark from 1990. The main outcomes were rates of psychiatric admissions, use of psychotropic medication, suicide attempts, suicides, patients in community-based private psychiatry or psychology practices and referrals to psychiatric hospitals. The impact of the pandemic (11 March 2020-30 June 2023) and lockdowns was assessed with log-normal models adjusted for pre-pandemic trends (1 January 2017-10 March 2020). We reported rate ratios (RR) of the observed and counterfactual rates. We identified the 5 807 714 (50.3% female) individuals living in Denmark on 1 March 2020. The rates of psychiatric admissions [RR: 0.95, 95% confidence interval (CI): 0.91 to 0.99, P-value: 0.017] and suicide attempts (RR: 0.85, 95% CI: 0.76 to 0.95, P-value: 0.007) were lower during the pandemic compared with the pre-pandemic trend. The rates of suicides (RR: 0.89, 95% CI: 0.75-1.05, P-value: 0.173), patients in private practices (RR: 1.00, 95% CI: 0.96-1.04, P-value: 0.986) and referrals (RR: 1.06, 95% CI: 0.95-1.18, P-value: 0.307) were not significantly different during the pandemic compared with the pre-pandemic trend. During the first lockdown, rates were lower for psychiatric admissions (RR: 0.85, 95% CI: 0.80 to 0.90, P-value <0.001), suicide attempts (RR: 0.80, 95% CI: 0.69 to 0.94, P-value: 0.007), suicides (RR: 0.67, 95% CI: 0.52 to 0.86, P-value: 0.002), patients in private practices (RR: 0.88, 95% CI: 0.82 to 0.93, P-value <0.001) and referrals (RR: 0.69, 95% CI: 0.60 to 0.81, P-value <0.001) compared with the pre-pandemic trend. However, during the pandemic, the rate of psychotropic medication users increased by 6% compared with the pre-pandemic trend (RR: 1.06, 95% CI: 1.05 to 1.06, P-value < 0.001). The COVID-19 pandemic and lockdowns did not severely influence pre-pandemic trends of the mental health burden in the population of Denmark on a nationwide level.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1829-1840"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590009","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}