Brain最新文献

{"title":"Cell-specific Eif2b5 mutant mice: novel insights into roles of macroglia in vanishing white matter","authors":"Javier Triñanes-Ramos, Marianna Bugiani, Gemma van Rooijen-van Leeuwen, Juliette A Chevalier, Yuan Jiew Siu, Elise L H van Utenhove, Leoni Hoogterp, Diede Witkamp, Ellen Oudejans, Bastiaan Lodder, Maarten Kole, Gesine Saher, Klaus-Armin Nave, Truus E M Abbink, Marjo S van der Knaap","doi":"10.1093/brain/awaf171","DOIUrl":"https://doi.org/10.1093/brain/awaf171","url":null,"abstract":"Vanishing white matter (VWM) is a leukodystrophy caused by mutations in any of the genes encoding the subunits of the eukaryotic translation initiation factor 2B (eIF2B), a central factor in mRNA translation initiation and regulator of the translation rate during the integrated stress response (ISR). Clinically, VWM is characterized by chronic motor and cognitive decline and premature death. Neuropathology shows selective white matter involvement with dysmorphic, immature astrocytes and defective reactive astrogliosis, while oligodendrocytes show increased expression of immaturity and proliferation markers and neurons look normal. The expression of the ATF4-transcriptome is increased in the white matter. These characteristics have been successfully replicated in eIF2B mutant mouse models. Until now, the relative contribution of each cell type to the development of VWM has remained unclear. Understanding the vulnerability of specific cell types for VWM is critical for understanding disease mechanisms and developing effective therapies. We generated astrocyte-, oligodendrocyte-, and neuron-specific Eif2b5 conditional mouse lines to determine the role of each mutant cell type in the onset and development of the disease. We evaluated motor performance, white matter pathology and the expression of myelin-related proteins. We analyzed astrocytes and oligodendrocytes density, maturity, morphology, proliferation, and apoptosis. We investigated the expression of the ISR-/ATF4-related genes and proteins, as well as their localization within the glial cells. At age 9 months, we found that astrocyte-specific Eif2b5 conditional mice showed very mild ataxia, extensive intramyelinic vacuolization, normal density and maturity of oligodendrocytes, and high expression of ATF4-related genes. Oligodendrocyte-specific Eif2b5 conditional mice developed gait ataxia that matched the phenotype of the whole-body Eif2b5 mutant line. Myelin looked normal, but numerous axons were unmyelinated; astrocytes were reactive, and oligodendrocytes were immature and in cell cycle. The enhanced ATF4-transcriptome was minor compared to the astrocyte-specific lines. The neuron-specific Eif2b5 conditional line exhibited a very mild phenotype and none of the major characteristic of VWM. Our findings highlight a complex effect of Eif2b5 mutations in different brain cell types leading to the clinical and neuropathological characteristics of VWM. Oligodendrocytes are the major contributors to the development of ataxia, but astrocyte-specific Eif2b5 conditional mice display several histological and molecular key features of VWM. In conclusion, the view of a single cell population being responsible for the onset and development of VWM needs to be replaced by the concept of VWM as a disease involving diverse cell types.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"24 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910341","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":"Beyond a syndrome: a mechanism for depression in Parkinson’s disease","authors":"Campbell Le Heron, Trevor T -J Chong","doi":"10.1093/brain/awaf165","DOIUrl":"https://doi.org/10.1093/brain/awaf165","url":null,"abstract":"This scientific commentary refers to ‘Impaired reward sensitivity in Parkinson’s depression is unresponsive to dopamine treatment’ by Costello et al. (https://doi.org/10.1093/brain/awaf098).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"110 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901814","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":"At-home wearables and machine learning capture motor impairment and progression in adult ataxias","authors":"Rohin Manohar, Faye X Yang, Christopher D Stephen, Jeremy D Schmahmann, Nicole M Eklund, Anoopum S Gupta","doi":"10.1093/brain/awaf154","DOIUrl":"https://doi.org/10.1093/brain/awaf154","url":null,"abstract":"A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior. Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T). Remotely collected cross-sectional (n = 76) and longitudinal data (n = 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, showed differences between ataxia and control groups with high effect size, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"28 26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893453","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":"Brain accumulation of lactosylceramide characterizes GALC deficiency in a zebrafish model of Krabbe disease","authors":"Jessica Guerra, Mirella Belleri, Elisa Scalvini, Davide Capoferri, Chiara Tobia, Cosetta Ravelli, Marzia Corli, Nicole Bresciani, Josefina Casas, Gemma Fabrias, Michele Dei Cas, Marco Presta, Luca Mignani","doi":"10.1093/brain/awaf150","DOIUrl":"https://doi.org/10.1093/brain/awaf150","url":null,"abstract":"Krabbe disease (KD) is an autosomal recessive sphingolipidosis due to mutations of the GALC gene encoding for the lysosomal β-galactosylceramidase (GALC) that removes β-galactose from β-galactosylceramide, β-lactosylceramide (LacCer), and the neurotoxic metabolite β-galactosylsphingosine (psychosine). At present, the accumulation of psychosine is thought to be the main cause of demyelination, neurodegeneration, and neuroinflammation that characterize the early infantile KD with a 1.5-2-year median survival. Currently, the standard of care of KD is hematopoietic stem cell transplantation which however improves the lifespan of Krabbe patients only when performed before symptoms outbreak. Thus, a better understanding of the pathogenesis of KD is required for the development of more efficacious therapeutic approaches. This largely depends upon the availability of novel suitable animal models of the disease. Zebrafish (Danio Rerio) represents a useful platform for the study of the mechanisms responsible for human hereditary diseases, including sphingolipidoses, and for the identification of new therapeutics. Two co-orthologs of human GALC have been identified in zebrafish, named galca and galcb. Here, we generated a mutant zebrafish line for each of the two co-orthologues by CRISPR/Cas9 genome editing. Galcb knockout (KO), but not galca KO, exerts a dramatic decrease of total GALC activity both in zebrafish embryos and in the brain of adult mutants. At 3-4 months post fertilization, galcb KO zebrafish showed impaired locomotion and reduced life span. Gene expression analysis, immunohistochemistry, spectral confocal reflectance, and transmission electron microscopy showed the presence of demyelination, neuroinflammation, and neurodegeneration in the brain of galcb KO mutants. Notably, double galca/galcb KO did not cause a further worsening of the disease when compared to galcb KO mutants. Finally, targeted lipidomic analysis demonstrated a dramatic accumulation of the bioactive sphingolipid LacCer in the brain of both galcb KO and double galca/galcb KO mutants with a modest increase of psychosine levels. Accordingly, activation of LacCer-related signaling occurs in the brain of galcb KO animals. Furthermore, intraventricular injection of LacCer upregulates the expression of various proinflammatory markers and increase mpeg1-positive macrophage infiltration in the brain of 5 dpf zebrafish embryos. In conclusion, galcb KO zebrafish recapitulates several pathological features of KD and is characterized by the accumulation of the bioactive LacCer. This model sheds new light on a possible role of LacCer as a neuroinflammatory/neurodegenerative metabolite in KD with implications for the development of novel therapeutic strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"56 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893490","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":"Pleiotropic effects of MORC2 derive from its epigenetic signature.","authors":"Fatemeh Peymani,Tomohiro Ebihara,Dmitrii Smirnov,Robert Kopajtich,Masahiro Ando,Enrico Bertini,Rosalba Carrozzo,Daria Diodato,Felix Distelmaier,Fang Fang,Daniele Ghezzi,Maja Hempel,Katarzyna Iwanicka-Pronicka,Thomas Klopstock,Sarah L Stenton,Costanza Lamperti,Zhimei Liu,Aysylu Murtazina,Yuji Okamoto,Yasushi Okazaki,Dorota Piekutowska-Abramczuk,Agnés Rötig,Oxana Ryzhkova,Christian Schlein,Olga Shagina,Hiroshi Takashima,Polina G Tsygankova,Michael Zech,Thomas Meitinger,Masaru Shimura,Kei Murayama,Holger Prokisch","doi":"10.1093/brain/awaf159","DOIUrl":"https://doi.org/10.1093/brain/awaf159","url":null,"abstract":"Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analyzed blood and fibroblast DNA methylation, transcriptomes, proteomes, and phenotypes of 53 MORC2 patients. We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes -ERCC8, NDUFAF2, and FKTN- at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8. Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"48 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893226","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":"Altered T-cell reactivity in the early stages of Alzheimer’s disease","authors":"Chiara Rickenbach, Anna Mallone, Lars Häusle, Larissa Frei, Sarina Seiter, Colin Sparano, Tunahan Kirabali, Kaj Blennow, Henrik Zetterberg, Maria Teresa Ferretti, Luka Kulic, Christoph Hock, Roger M Nitsch, Valerie Treyer, Anton Gietl, Christoph Gericke","doi":"10.1093/brain/awaf167","DOIUrl":"https://doi.org/10.1093/brain/awaf167","url":null,"abstract":"The adaptive immune system and neurodegenerative Alzheimer’s disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, ex vivo T-cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards β-amyloid peptide and display an early enrichment of CD8+ T effector memory cells re-expressing CD45RA (TEMRA cells) in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T-cells. Conversely, in MCI we observed increased frequencies of CD8+ TEMRA/effector cells in the periphery characterized by a pro-inflammatory gene expression profile, and generally decreased antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial to promote specific CD4+ T-cell responses in the preclinical stage, while in MCI it may be important to therapeutically target CD8+ T-cell responses if these prove to be harmful.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"9 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910336","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":"Disruption of DNA methylation underpins the neuroinflammation induced by targeted CNS radiotherapy","authors":"Thomas O Millner, Pratistha Panday, Yunchen Xiao, James Nicholson, James R Boot, Zsharmaine Arpe, Paul A Stevens, Nadia N Rahman, Xinyu Zhang, Charles Mein, Neil Kitchen, Andrew W McEvoy, Edward McKintosh, Grainne S McKenna, Dimitrios Paraskevopoulos, Nicolae Radu Zabet, Rachel Lewis, Sara Badodi, Silvia Marino","doi":"10.1093/brain/awaf163","DOIUrl":"https://doi.org/10.1093/brain/awaf163","url":null,"abstract":"Targeted radiotherapy (RT) is integral to the increasing survival of cancer patients; however, it has significant side-effects, the underlying cellular and molecular mechanisms of which are ill-defined. It is well documented that RT induces epigenetic changes in neoplastic tissue, which impacts tumour evolution, however whether epigenetic deregulation also occurs in the surrounding non-neoplastic tissue and contributes to the occurrence of side effects is unknown. We characterised the DNA methylome in a unique cohort of irradiated peri-lesional brain tissue samples and integrated it with gene expression analysis at the spatial level. We show differences in DNA methylation patterns in irradiated brain tissue and identify specific inflammatory micro-environmental niches and their regulatory neuropeptides after irradiation. Finally, we show in a cerebral organoid model, that the same neuropeptides are upregulated as well as similar DNA methylation alterations and disruption of the DNA methylation machinery, in keeping with the interpretation that epigenetic dysregulation plays a role in neurotoxicity, hence raising the possibility it could represent a novel target for the reduction of radiotherapy side-effects.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"11 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884828","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: Nigrostriatal tau pathology in parkinsonism and Parkinson's disease.","authors":"","doi":"10.1093/brain/awaf146","DOIUrl":"https://doi.org/10.1093/brain/awaf146","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889220","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":"Making a diagnosis of Alzheimer's disease in asymptomatic individuals with positive biomarkers","authors":"Nunzio Pomara, Bruno Pietro Imbimbo","doi":"10.1093/brain/awaf162","DOIUrl":"https://doi.org/10.1093/brain/awaf162","url":null,"abstract":"About 25% of cognitively unimpaired older adults have an elevated brain amyloid burden comparable to that of individuals with symptomatic Alzheimer’s disease. Pomara and Imbimbo examine the ongoing debate over whether these individuals should be classified as having preclinical Alzheimer’s disease or simply be considered ‘at risk’.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"7 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880373","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":"Emerging roles of transfer RNA fragments in the CNS","authors":"Katarzyna Winek, Hermona Soreq","doi":"10.1093/brain/awaf130","DOIUrl":"https://doi.org/10.1093/brain/awaf130","url":null,"abstract":"tRNA-derived small RNAs (tsRNAs), previously considered inactive tRNA degradation products, have now been shown to be functional small noncoding RNAs. They may play important roles within the central nervous system (CNS) and in brain-body interactions both during normal developmental stages as well as in diverse brain pathologies. Among the cell types found in the CNS, tsRNAs are most abundant in neurons. Correspondingly, neurons show cell type specific tRNA expression profiles when compared to other cells of the CNS under homeostatic conditions and defects in tRNA processing may lead to neurological disorders. Disease-specific tsRNA profiles have been identified in a number of CNS disorders including amyotrophic lateral sclerosis (ALS) and epilepsy. Elevated levels of specific tsRNAs have been found in the blood before the onset of epileptic seizures, and age-related, sex-specific loss of mitochondrial genome-originated tsRNAs in the nucleus accumbens of female patients is correlated to accelerated cognitive deterioration in Alzheimer’s disease. Disease-related tsRNA signatures have also been identified in the cerebrospinal fluid of Parkinson’s disease patients, and nucleated blood cells from ischemic stroke patients show specific elevation of cholinergic-targeted tsRNAs. The mechanisms of action of tsRNAs are still being elucidated but include targeting complementary mRNA to impact RNA levels and translation in a miRNA-like manner, direct interaction with RNA binding proteins, or interference with translation machinery. The function of tsRNAs may be affected by the chemical modifications they inherit from the originating tRNA molecules, which impact tsRNAs production and may modulate their interactions with proteins. Research on the genetics, biochemical properties and regulatory roles of tsRNAs has expanded rapidly in recent years, facilitated by novel sequencing strategies which include the removal of tRNA modifications and chemically blocked ends that hinder amplification and adapter ligation. Future in-depth profiling of tsRNAs levels, mode/s of function, and identification of interacting proteins and RNAs may together shed light on the tsRNAs impact on neuronal function, and enable novel diagnostics/therapeutics avenues for brain diseases in age, sex and disease-specific manner.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"8 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884833","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}