Pub Date : 2024-09-14DOI: 10.1016/j.nbd.2024.106668
Cockayne syndrome (CS) is an autosomal recessive disorder of developmental delay, multiple organ system degeneration and signs of premature ageing. We show here, using the RNA-seq data from two CS mutant cell lines, that the CS key transcriptional signature displays significant enrichment of neurodegeneration terms, including genes relevant in Huntington disease (HD). By using deep learning approaches and two published RNA-Seq datasets, the CS transcriptional signature highly significantly classified and predicted HD and control samples. Neurodegeneration is one hallmark of CS disease, and fibroblasts from CS patients with different causative mutations display disturbed ribosomal biogenesis and a consecutive loss of protein homeostasis - proteostasis. Encouraged by the transcriptomic data, we asked whether this pathomechanism is also active in HD. In different HD cell-culture models, we showed that mutant Huntingtin impacts ribosomal biogenesis and function. This led to an error-prone protein synthesis and, as shown in different mouse models and human tissue, whole proteome instability, and a general loss of proteostasis.
科克恩综合征(Cockayne syndrome,CS)是一种常染色体隐性遗传疾病,患者会出现发育迟缓、多器官系统退化和早衰症状。我们在此利用两个CS突变细胞系的RNA-seq数据表明,CS关键转录特征显示了神经变性术语的显著富集,包括与亨廷顿病(HD)相关的基因。通过使用深度学习方法和两个已发表的 RNA-Seq 数据集,CS 转录特征对 HD 和对照样本进行了高度显著的分类和预测。神经退行性变是CS疾病的标志之一,不同致病突变的CS患者的成纤维细胞显示出核糖体生物发生紊乱和蛋白质稳态(蛋白稳态)的连续丧失。在转录组数据的鼓舞下,我们询问这种病理机制是否也在 HD 中活跃。在不同的 HD 细胞培养模型中,我们发现突变型亨廷汀会影响核糖体的生物发生和功能。这导致了易出错的蛋白质合成,正如在不同的小鼠模型和人体组织中显示的那样,导致了整个蛋白质组的不稳定性和蛋白质稳态的普遍丧失。
{"title":"General loss of proteostasis links Huntington disease to Cockayne syndrome","authors":"","doi":"10.1016/j.nbd.2024.106668","DOIUrl":"10.1016/j.nbd.2024.106668","url":null,"abstract":"<div><p>Cockayne syndrome (CS) is an autosomal recessive disorder of developmental delay, multiple organ system degeneration and signs of premature ageing. We show here, using the RNA-seq data from two CS mutant cell lines, that the CS key transcriptional signature displays significant enrichment of neurodegeneration terms, including genes relevant in Huntington disease (HD). By using deep learning approaches and two published RNA-Seq datasets, the CS transcriptional signature highly significantly classified and predicted HD and control samples. Neurodegeneration is one hallmark of CS disease, and fibroblasts from CS patients with different causative mutations display disturbed ribosomal biogenesis and a consecutive loss of protein homeostasis - proteostasis. Encouraged by the transcriptomic data, we asked whether this pathomechanism is also active in HD. In different HD cell-culture models, we showed that mutant Huntingtin impacts ribosomal biogenesis and function. This led to an error-prone protein synthesis and, as shown in different mouse models and human tissue, whole proteome instability, and a general loss of proteostasis.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002687/pdfft?md5=8e000560ce6f970b2ff07fd8eac29388&pid=1-s2.0-S0969996124002687-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-14DOI: 10.1016/j.nbd.2024.106667
Huntington's Disease (HD) is an inheritable neurodegenerative condition caused by an expanded CAG trinucleotide repeat in the HTT gene with a direct correlation between CAG repeats expansion and disease severity with earlier onset-of- disease. Previously we have shown that primary skin fibroblasts from HD patients exhibit unique phenotype disease features, including distinct nuclear morphology and perturbed actin cap linked with cell motility, that are correlated with the HD patient disease severity. Here we provide further evidence that mitochondrial fission-fusion morphology balance dynamics, classified using a custom image-based high-content analysis (HCA) machine learning tool, that improved correlation with HD severity status. This mitochondrial phenotype is supported by appropriate changes in fission-fusion biomarkers (Drp1, MFN1, MFN2, VAT1) levels in the HD patients' fibroblasts. These findings collectively point towards a dysregulation in mitochondrial dynamics, where both fission and fusion processes may be disrupted in HD cells compared to healthy controls. This study shows for the first time a methodology that enables identification of HD phenotype before patient's disease onset (Premanifest). Therefore, we believe that this tool holds a potential for improving precision in HD patient's diagnostics bearing the potential to evaluate alterations in mitochondrial dynamics throughout the progression of HD, offering valuable insights into the molecular mechanisms and drug therapy evaluation underlying biological differences in any disease stage.
亨廷顿氏病(Huntington's Disease,HD)是一种可遗传的神经退行性疾病,由 HTT 基因中的 CAG 三核苷酸重复序列扩增引起。此前我们已经证明,HD 患者的原代皮肤成纤维细胞表现出独特的表型疾病特征,包括独特的核形态和与细胞运动相关的肌动蛋白帽紊乱,这些特征与 HD 患者的疾病严重程度相关。在这里,我们提供了线粒体裂变融合形态平衡动态的进一步证据,该动态是利用定制的基于图像的高内容分析(HCA)机器学习工具进行分类的,它与 HD 严重程度状态的相关性得到了改善。HD患者成纤维细胞中裂变融合生物标志物(Drp1、MFN1、MFN2、VAT1)水平的适当变化也支持这种线粒体表型。这些发现共同指向线粒体动力学失调,与健康对照组相比,HD 细胞的裂变和融合过程都可能受到破坏。这项研究首次展示了一种能在患者发病前识别 HD 表型的方法(Premanifest)。因此,我们认为该工具具有提高 HD 患者诊断精确度的潜力,可评估 HD 病程发展过程中线粒体动力学的变化,为了解任何疾病阶段的分子机制和药物治疗评估提供有价值的信息。
{"title":"Characterization of fission and fusion mitochondrial dynamics in HD fibroblasts according to patient's severity status","authors":"","doi":"10.1016/j.nbd.2024.106667","DOIUrl":"10.1016/j.nbd.2024.106667","url":null,"abstract":"<div><p>Huntington's Disease (HD) is an inheritable neurodegenerative condition caused by an expanded CAG trinucleotide repeat in the HTT gene with a direct correlation between CAG repeats expansion and disease severity with earlier onset-of- disease. Previously we have shown that primary skin fibroblasts from HD patients exhibit unique phenotype disease features, including distinct nuclear morphology and perturbed actin cap linked with cell motility, that are correlated with the HD patient disease severity. Here we provide further evidence that mitochondrial fission-fusion morphology balance dynamics, classified using a custom image-based high-content analysis (HCA) machine learning tool, that improved correlation with HD severity status. This mitochondrial phenotype is supported by appropriate changes in fission-fusion biomarkers (Drp1, MFN1, MFN2, VAT1) levels in the HD patients' fibroblasts. These findings collectively point towards a dysregulation in mitochondrial dynamics, where both fission and fusion processes may be disrupted in HD cells compared to healthy controls. This study shows for the first time a methodology that enables identification of HD phenotype before patient's disease onset (Premanifest). Therefore, we believe that this tool holds a potential for improving precision in HD patient's diagnostics bearing the potential to evaluate alterations in mitochondrial dynamics throughout the progression of HD, offering valuable insights into the molecular mechanisms and drug therapy evaluation underlying biological differences in any disease stage.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002675/pdfft?md5=12bff562c80f77e9962bcc94cdc581ed&pid=1-s2.0-S0969996124002675-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-14DOI: 10.1016/j.nbd.2024.106666
Kenji Hashimoto, Yan Wei, Chun Yang
{"title":"Special issue on “A focus on brain–body communication in understanding the neurobiology of diseases”","authors":"Kenji Hashimoto, Yan Wei, Chun Yang","doi":"10.1016/j.nbd.2024.106666","DOIUrl":"https://doi.org/10.1016/j.nbd.2024.106666","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1016/j.nbd.2024.106664
AMP-activated protein kinase (AMPK) is an αβγ heterotrimer protein kinase that functions as a molecular sensor to maintain energy homeostasis. Accumulating evidence suggests a role of AMPK signaling in the regulation of synaptic plasticity and cognitive function; however, isoform-specific roles of AMPK in the central nervous system (CNS) remain elusive. Regulation of the AMPK activities has focused on the manipulation of the α or γ subunit. Meanwhile, accumulating evidence indicates that the β subunit is critical for sensing nutrients such as fatty acids and glycogen to control AMPK activity. Here, we generated transgenic mice with conditional suppression of either AMPKβ1 or β2 in neurons and characterized potential isoform-specific roles of AMPKβ in cognitive function and underlying mechanisms. We found that AMPKβ2 (but not β1) suppression resulted in impaired recognition memory, reduced hippocampal synaptic plasticity, and altered structure of hippocampal postsynaptic densities and dendritic spines. Our study implicates a role for the AMPKβ2 isoform in the regulation of synaptic and cognitive function.
{"title":"Suppression of neuronal AMPKβ2 isoform impairs recognition memory and synaptic plasticity","authors":"","doi":"10.1016/j.nbd.2024.106664","DOIUrl":"10.1016/j.nbd.2024.106664","url":null,"abstract":"<div><p>AMP-activated protein kinase (AMPK) is an αβγ heterotrimer protein kinase that functions as a molecular sensor to maintain energy homeostasis. Accumulating evidence suggests a role of AMPK signaling in the regulation of synaptic plasticity and cognitive function; however, isoform-specific roles of AMPK in the central nervous system (CNS) remain elusive. Regulation of the AMPK activities has focused on the manipulation of the α or γ subunit. Meanwhile, accumulating evidence indicates that the β subunit is critical for sensing nutrients such as fatty acids and glycogen to control AMPK activity. Here, we generated transgenic mice with conditional suppression of either AMPKβ1 or β2 in neurons and characterized potential isoform-specific roles of AMPKβ in cognitive function and underlying mechanisms. We found that AMPKβ2 (but not β1) suppression resulted in impaired recognition memory, reduced hippocampal synaptic plasticity, and altered structure of hippocampal postsynaptic densities and dendritic spines. Our study implicates a role for the AMPKβ2 isoform in the regulation of synaptic and cognitive function.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S096999612400264X/pdfft?md5=7d946ab6bfa82e29d26cd5dabb5bdc31&pid=1-s2.0-S096999612400264X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1016/j.nbd.2024.106665
Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms.
This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months' follow-up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or > 50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0–2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes.
Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h.
In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.
循环细胞外囊泡(EVs)可参与脑内出血(ICH)后引发的先天性修复过程。我们的目的是描述 ICH 急性期和亚急性期之间循环 EVs 蛋白体谱的变化,并根据不同的结果对研究结果进行比较,从而揭示这种修复机制。排除标准为既往残疾、基线计算机断层扫描有疝气迹象或预期寿命有限。分别在症状出现后的 24 小时和 7 天从血液样本中分离出 EVs。经过6个月的随访,患者被分为预后差和预后好两种,预后好的定义是在美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale)上评分提高了10分或50%,修改后的兰金量表(Modified Rankin Scale)评分提高了0-2分。44名患者完成了随访,其中16人(35.5%)的随访结果良好。我们在 EVs 中发现了 1321 种蛋白质,其中 37 种蛋白质的丰度存在差异。在预后良好的患者中,与应激反应(DERA、VNN2、TOMM34)和血管生成(RHG01)相关的蛋白质在7天后丰度增加。总之,ICH 患者循环 EVs 中的蛋白质含量会随着时间的推移而变化,其变化因临床结果而异,结果良好的患者中可能参与修复过程的蛋白质含量更高。
{"title":"The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery","authors":"","doi":"10.1016/j.nbd.2024.106665","DOIUrl":"10.1016/j.nbd.2024.106665","url":null,"abstract":"<div><p>Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms.</p><p>This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months' follow-up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or > 50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0–2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes.</p><p>Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h.</p><p>In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002651/pdfft?md5=9894e0b83d52f843d0c6561f63f29d6b&pid=1-s2.0-S0969996124002651-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1016/j.nbd.2024.106663
The functionality of the central nervous system (CNS) relies on the connection, integration, and the exchange of information among neural cells. The crosstalk among glial cells and neurons is pivotal for a series of neural functions, such as development of the nervous system, electric conduction, synaptic transmission, neural circuit establishment, and brain homeostasis. Glial cells are crucial players in the maintenance of brain functionality in physiological and disease conditions. Neuroinflammation is a common pathological process in various brain disorders, such as neurodegenerative diseases, and infections. Glial cells, including astrocytes, microglia, and oligodendrocytes, are the main mediators of neuroinflammation, as they can sense and respond to brain insults by releasing pro-inflammatory or anti-inflammatory factors. Recent evidence indicates that extracellular vesicles (EVs) are pivotal players in the intercellular communication that underlies physiological and pathological processes. In particular, glia-derived EVs play relevant roles in modulating neuroinflammation, either by promoting or inhibiting the activation of glial cells and neurons, or by facilitating the clearance or propagation of pathogenic proteins. The involvement of EVs in neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Multiple Sclerosis (MS)- which share hallmarks such as neuroinflammation and oxidative stress to DNA damage, alterations in neurotrophin levels, mitochondrial impairment, and altered protein dynamics- will be dissected, showing how EVs act as pivotal cell-cell mediators of toxic stimuli, thereby propagating degeneration and cell death signaling. Thus, this review focuses on the EVs secreted by microglia, astrocytes, oligodendrocytes and in neuroinflammatory conditions, emphasizing on their effects on neurons and on central nervous system functions, considering both their beneficial and detrimental effects.
{"title":"Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles","authors":"","doi":"10.1016/j.nbd.2024.106663","DOIUrl":"10.1016/j.nbd.2024.106663","url":null,"abstract":"<div><p>The functionality of the central nervous system (CNS) relies on the connection, integration, and the exchange of information among neural cells. The crosstalk among glial cells and neurons is pivotal for a series of neural functions, such as development of the nervous system, electric conduction, synaptic transmission, neural circuit establishment, and brain homeostasis. Glial cells are crucial players in the maintenance of brain functionality in physiological and disease conditions. Neuroinflammation is a common pathological process in various brain disorders, such as neurodegenerative diseases, and infections. Glial cells, including astrocytes, microglia, and oligodendrocytes, are the main mediators of neuroinflammation, as they can sense and respond to brain insults by releasing pro-inflammatory or anti-inflammatory factors. Recent evidence indicates that extracellular vesicles (EVs) are pivotal players in the intercellular communication that underlies physiological and pathological processes. In particular, glia-derived EVs play relevant roles in modulating neuroinflammation, either by promoting or inhibiting the activation of glial cells and neurons, or by facilitating the clearance or propagation of pathogenic proteins. The involvement of EVs in neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Multiple Sclerosis (MS)- which share hallmarks such as neuroinflammation and oxidative stress to DNA damage, alterations in neurotrophin levels, mitochondrial impairment, and altered protein dynamics- will be dissected, showing how EVs act as pivotal cell-cell mediators of toxic stimuli, thereby propagating degeneration and cell death signaling. Thus, this review focuses on the EVs secreted by microglia, astrocytes, oligodendrocytes and in neuroinflammatory conditions, emphasizing on their effects on neurons and on central nervous system functions, considering both their beneficial and detrimental effects.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002638/pdfft?md5=998d9c96ac4708a05c2501013088cba1&pid=1-s2.0-S0969996124002638-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.nbd.2024.106659
Aim
Parkinson's disease (PD) tremor is associated with dysfunction in the basal ganglia (BG), cerebellum (CB), and sensorimotor networks (SMN). We investigated tremor-related static functional network connectivity (SFNC) and dynamic functional network connectivity (DFNC) in PD patients.
Methods
We analyzed the resting-state functional MRI data of 21 tremor-dominant Parkinson's disease (TDPD) patients and 29 healthy controls. We compared DFNC and SFNC between the three networks and assessed their associations with tremor severity.
Results
TDPD patients exhibited increased SFNC between the SMN and BG networks. In addition, they spent more mean dwell time (MDT) in state 2, characterized by sparse connections, and less MDT in state 4, indicating stronger connections. Furthermore, enhanced DFNC between the CB and SMN was observed in state 2. Notably, the MDT of state 2 was positively associated with tremor scores.
Conclusion
The enhanced dynamic connectivity between the CB and SMN in TDPD patients suggests a potential compensatory mechanism. However, the tendency to remain in a state of sparse connectivity may contribute to the severity of tremor symptoms.
{"title":"Dynamic cerebellar and sensorimotor network compensation in tremor-dominated Parkinson's disease","authors":"","doi":"10.1016/j.nbd.2024.106659","DOIUrl":"10.1016/j.nbd.2024.106659","url":null,"abstract":"<div><h3>Aim</h3><p>Parkinson's disease (PD) tremor is associated with dysfunction in the basal ganglia (BG), cerebellum (CB), and sensorimotor networks (SMN). We investigated tremor-related static functional network connectivity (SFNC) and dynamic functional network connectivity (DFNC) in PD patients.</p></div><div><h3>Methods</h3><p>We analyzed the resting-state functional MRI data of 21 tremor-dominant Parkinson's disease (TDPD) patients and 29 healthy controls. We compared DFNC and SFNC between the three networks and assessed their associations with tremor severity.</p></div><div><h3>Results</h3><p>TDPD patients exhibited increased SFNC between the SMN and BG networks. In addition, they spent more mean dwell time (MDT) in state 2, characterized by sparse connections, and less MDT in state 4, indicating stronger connections. Furthermore, enhanced DFNC between the CB and SMN was observed in state 2. Notably, the MDT of state 2 was positively associated with tremor scores.</p></div><div><h3>Conclusion</h3><p>The enhanced dynamic connectivity between the CB and SMN in TDPD patients suggests a potential compensatory mechanism. However, the tendency to remain in a state of sparse connectivity may contribute to the severity of tremor symptoms.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002596/pdfft?md5=a037b397c03c50a57b2d79f0f569dba7&pid=1-s2.0-S0969996124002596-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.nbd.2024.106658
Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the thyroid gland to produce and release thyroid hormones, primarily thyroxine and triiodothyronine. These hormones are key players in body–brain communication, influencing various physiological processes, including the regulation of metabolism (both peripheral and central effects), feedback mechanisms, and lipid metabolism. Recently, the increasing incidence of abnormal lipid metabolism has highlighted the link between thyroid function and lipid metabolism. Evidence suggests that TSH can affect all bodily systems through body–brain communication, playing a crucial role in growth, development, and the regulation of various physiological systems. Lipids serve dual purposes: they are involved in energy storage and metabolism, and they act as vital signaling molecules in numerous cellular activities, maintaining overall human health or contributing to various diseases. This article reviews the role of TSH in regulating lipid metabolism via body–brain crosstalk, focusing on its implications for common lipid metabolism disorders such as obesity, atherosclerosis, nonalcoholic fatty liver disease, neuropsychiatric disorders (including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and depression), and cerebrovascular disorders such as stroke.
{"title":"The role of thyroid-stimulating hormone in regulating lipid metabolism: Implications for body–brain communication","authors":"","doi":"10.1016/j.nbd.2024.106658","DOIUrl":"10.1016/j.nbd.2024.106658","url":null,"abstract":"<div><p>Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the thyroid gland to produce and release thyroid hormones, primarily thyroxine and triiodothyronine. These hormones are key players in body–brain communication, influencing various physiological processes, including the regulation of metabolism (both peripheral and central effects), feedback mechanisms, and lipid metabolism. Recently, the increasing incidence of abnormal lipid metabolism has highlighted the link between thyroid function and lipid metabolism. Evidence suggests that TSH can affect all bodily systems through body–brain communication, playing a crucial role in growth, development, and the regulation of various physiological systems. Lipids serve dual purposes: they are involved in energy storage and metabolism, and they act as vital signaling molecules in numerous cellular activities, maintaining overall human health or contributing to various diseases. This article reviews the role of TSH in regulating lipid metabolism via body–brain crosstalk, focusing on its implications for common lipid metabolism disorders such as obesity, atherosclerosis, nonalcoholic fatty liver disease, neuropsychiatric disorders (including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and depression), and cerebrovascular disorders such as stroke.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002584/pdfft?md5=eb11144af24c156c51e2527585f6aa47&pid=1-s2.0-S0969996124002584-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.nbd.2024.106657
Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2, which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic Slc35a2 knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies.
{"title":"Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing","authors":"","doi":"10.1016/j.nbd.2024.106657","DOIUrl":"10.1016/j.nbd.2024.106657","url":null,"abstract":"<div><p>Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in <em>SLC35A2</em>, which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout <em>Slc35a2</em> in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic <em>Slc35a2</em> knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic <em>Slc35a2</em> knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with <em>Slc35a2</em> knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that <em>Slc35a2</em> knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic <em>Slc35a2</em> knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic <em>Slc35a2</em> deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002572/pdfft?md5=3bac71749dc9a9d7f67df4cf5ce4bd74&pid=1-s2.0-S0969996124002572-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1016/j.nbd.2024.106656
Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors—BAY 61–3606 and R406—on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3β expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.
{"title":"Syk inhibitors reduce tau protein phosphorylation and oligomerization","authors":"","doi":"10.1016/j.nbd.2024.106656","DOIUrl":"10.1016/j.nbd.2024.106656","url":null,"abstract":"<div><p>Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors—BAY 61–3606 and R406—on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated <em>in vivo</em> using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3β expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. <em>In vivo</em>, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002560/pdfft?md5=31f51f123c86c5c69a0aed208bf409d4&pid=1-s2.0-S0969996124002560-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}