Brain最新文献

{"title":"Medial temporal lobe structural changes when Down syndrome and Alzheimer's disease collide.","authors":"Laura E M Wisse,Renaud La Joie","doi":"10.1093/brain/awaf176","DOIUrl":"https://doi.org/10.1093/brain/awaf176","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"3 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945553","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":"Filamin A in focus: unravelling the multifaceted roles of filamin A in neurodevelopment and neurological disorders.","authors":"Longbo Zhang","doi":"10.1093/brain/awaf180","DOIUrl":"https://doi.org/10.1093/brain/awaf180","url":null,"abstract":"Neurodevelopment is an intricate process encompassing the proliferation, differentiation, migration, and maturation of neural cells. Disruptions in these tightly regulated events can lead to a variety of neurodevelopmental disorders. Filamin A (FLNA), a key actin-binding protein, plays a pivotal role in regulating neuronal migration, morphological development, and synaptic connectivity by modulating actin cytoskeletal dynamics and interacting with various signaling pathways. FLNA mutations are implicated in several neurodevelopmental disorders, such as periventricular nodular heterotopia (PVNH), leading to neurological symptoms such as epilepsy, intellectual disability, and cognitive impairments. In this review, we delve into FLNA's multifaceted role in neurodevelopment, with a particular focus on its contributions to neuronal migration, dendritic and axonal growth, and mechanotransduction. Additionally, we examine how FLNA dysregulation leads to neurodevelopmental abnormalities, providing insights into its potential as a therapeutic target. By elucidating the molecular mechanisms through which FLNA governs neurodevelopment, we aim to advance our understanding of its crucial role in both brain formation and disease pathogenesis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"27 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945554","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":"Souvenirs of an awake craniotomy","authors":"Camille Bégin","doi":"10.1093/brain/awaf124","DOIUrl":"https://doi.org/10.1093/brain/awaf124","url":null,"abstract":"What do you, a bilingual person, do when a surgeon asks which language you wish to keep as he is about to perform an awake craniotomy to remove your right frontal lobe brain tumour? Winner of the Brain Essay Competition 2024, Camille Bégin shares her personal experience of brain surgery.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"3 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946021","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":"AAV-based TCAP delivery rescues mitochondria dislocation in limb-girdle muscular dystrophy R7.","authors":"Xiaoqing Lv, Shuangwu Liu, Xi Li, He Lv, Kai Shao, Sushan Luo, Dandan Zhao, Chuanzhu Yan, Pengfei Lin","doi":"10.1093/brain/awae351","DOIUrl":"10.1093/brain/awae351","url":null,"abstract":"<p><p>Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fibre size variation, nuclear centralization and abnormal mitochondrial distribution. The mechanisms underlying this disease are unclear and there is currently no specific treatment for limb-girdle muscular dystrophy R7. This study established a Tcap-deficient mouse model to explore the disease mechanism of mitochondria dislocation and potential therapeutic strategies. We used methods such as proteomics, immunofluorescence, histopathological staining and western blotting to explore the mechanism of mitochondrial dislocation. Moreover, in the quest for a prospective therapeutic intervention for this disorder, the adeno-associated virus (AAV) serotype 2/9 was employed to deliver the Tcap gene into the muscles of these mice, facilitating preclinical experimentation. After 2 months and 7 months, the muscular phenotype was evaluated and selected mice were humanely euthanized for subsequent molecular and histological analysis. The phenotype of Tcap-/- mice mimicked that observed in individuals diagnosed with limb-girdle muscular dystrophy R7. This study elucidated the mechanism of mitochondrial dislocation in limb-girdle muscular dystrophy R7. Through our in vitro experiments, we discovered that telethonin aids in preserving the integrity of desmin by preventing truncation at the N-terminus. Additionally, telethonin combined with desmin and co-localized at the Z-disc. Research has shown that the Tcap gene plays a crucial role in controlling the desmin cytoskeleton organization. The absence of telethonin leads to a collapsed desmin cytoskeleton. This causes disorganization of the mitochondrial network, leading to mitochondrial dysfunction. In addition, the study investigated the efficacy of AAV-mediated Tcap replacement in Tcap-/- mice. By intramuscular delivery of AAV, we observed dramatic improvements in muscle phenotype, muscle pathology, CK levels, muscle MRI, mitochondrial network organization and mitochondrial function. The results of this study demonstrated that telethonin deficiency led to desmin cytoskeleton collapse that caused mitochondrial dislocation. AAV-mediated replacement therapy could be a promising safe and efficient treatment option for limb-girdle muscular dystrophy R7. The study highlights the potential of AAV-mediated replacement therapy for specific types of limb-girdle muscular dystrophy.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1680-1694"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520989","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":"Vascular health has an impact on brain health.","authors":"Masud Husain","doi":"10.1093/brain/awaf126","DOIUrl":"https://doi.org/10.1093/brain/awaf126","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"142 1","pages":"1439-1440"},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945555","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":"10.1093/brain/awaf049","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e39-e40"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","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":"Bullshit jobs and bullshit job holders: a defence.","authors":"Rachel M Msetfi,Diana E Kornbrot","doi":"10.1093/brain/awaf140","DOIUrl":"https://doi.org/10.1093/brain/awaf140","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"3 1","pages":"e45-e47"},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945560","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 bugs to brain: unravelling the GABA signalling networks in the brain-gut-microbiome axis.","authors":"Delia Belelli, Jeremy J Lambert, Murphy Lam Yim Wan, Ana Rita Monteiro, David J Nutt, Jerome D Swinny","doi":"10.1093/brain/awae413","DOIUrl":"10.1093/brain/awae413","url":null,"abstract":"<p><p>Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species. We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1479-1506"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12074267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881268","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":"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}