BIN1

BIN1
  • 文章类型: Journal Article
    据报道,桥接整合因子1(BIN1)基因多态性在阿尔茨海默病(AD)的病理过程中起作用。
    探讨BIN1位点与神经炎症和AD病理的关系。
    阿尔茨海默病神经影像学倡议(ADNI,N=495)是发现队列,和中国阿尔茨海默氏症的生物标志物和生活方式(电缆,N=619)研究用于复制结果。剖析中包含两个BIN1基因多态性(rs7561528和rs744373)。通过10,000次自举迭代进行的多重线性回归模型和因果调解分析用于检查BIN1基因座与脑脊液(CSF)AD生物标志物和在骨髓细胞2上表达的小胶质细胞活化小胶质细胞可溶性触发受体的替代生物标志物的关系(sTREM2)。
    在ADNI数据库中,我们发现BIN1基因座(rs7561528和rs744373)与CSF磷酸化tau(P-tau)水平(pc=0.017;0.010)和总tau(T-tau)水平(pc=0.011;0.013)之间存在显著关联.BIN1基因座也与CSFsTREM2水平相关(pc=0.010;0.008,分别)。中介分析表明,CSFsTREM2部分介导了BIN1基因座与P-tau(rs7561528比例:20.8%;rs744373比例:24.8%)和T-tau(rs7561528比例:36.5%;rs744373比例:43.9%)的关联。CABLE研究中的分析复制了rs7561528的中介作用。
    这项研究证明了BIN1基因座与CSFAD生物标志物以及小胶质细胞生物标志物之间的相关性。此外,BIN1基因座与tau病理之间的联系部分由CSFsTREM2介导。
    UNASSIGNED: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer\'s disease (AD).
    UNASSIGNED: To explore the association of BIN1 loci with neuroinflammation and AD pathology.
    UNASSIGNED: Alzheimer\'s Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and Chinese Alzheimer\'s Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2).
    UNASSIGNED: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc = 0.017; 0.010, respectively) and total-tau (T-tau) (pc = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528.
    UNASSIGNED: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.
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  • 文章类型: Journal Article
    全基因组关联研究确定BIN1(桥接整合因子1)基因位点周围的变异是晚发性阿尔茨海默病的主要危险因素。在本研究中,我们降低了BIN1在小鼠海马神经元中的表达,以研究其神经元功能。通过RNAi敲除Bin1可减少原代培养的海马神经元以及成熟的CornuAmmonis1兴奋性神经元的树突状乔木大小。AAV介导的Bin1RNAi敲除还在器官水平的注射部位周围产生了显着的区域体积损失,正如7特斯拉结构磁共振成像所揭示的那样,和巴恩斯迷宫测试中受损的空间参考记忆性能。出乎意料的是,Bin1敲低导致巨自噬/自噬和MTOR(雷帕霉素激酶的机制靶标)复合物1(MTORC1)的同时激活。溶酶体抑制剂氯喹的自噬抑制有效地减轻了Bin1敲低诱导的树突状消退。随后的分子研究表明,ULK3(unc-51样激酶3)的表达增加,它对MTOR不敏感,在BIN1缺乏症中支持自噬体形成。用受体酪氨酸激酶抑制剂SU6668降低ULK3活性,或通过AAV介导的RNAi降低神经元ULK3表达,显着减轻Bin1敲低诱导的海马体积损失和空间记忆下降。在阿尔茨海默病患者中,BIN1的主要神经元同工型被特异性减少。我们的工作表明,这种减少可能是增加自噬水平的重要分子事件,这可能会通过减少树突结构来促进脑萎缩和认知障碍,和ULK3是缓解这些有害影响的潜在干预目标。
    Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular studydemonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.Abbreviations: AV: adeno-associated virus; Aβ: amyloid-β; ACTB: actin, beta; AD: Alzheimer disease; Aduk: Another Drosophila Unc-51-like kinase; AKT1: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; AP: autophagosome; BafA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BIN1: bridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco\'s modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance imaging; MTOR; mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PET: positron emission tomography; qRT-PCR: real-time quantitative reverse transcription PCR; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; TFEB: transcription factor EB; ULK1: unc-51 like kinase 1; ULK3: unc-51 like kinase 3.
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  • 文章类型: Journal Article
    膜重塑的蛋白质-蛋白质相互作用SH3结构域的截短桥接整合因子1(BIN1,Amphiphysin2)蛋白导致中心核肌病。这里,我们评估了一组自然观察到的影响,先前未表征的BIN1SH3结构域变体使用常规的体外和基于细胞的测定法监测BIN1与动力蛋白2(DNM2)的相互作用,并鉴定了可能与神经肌肉疾病有关的潜在有害变体。然而,SH3域通常是混杂的,预计其他,迄今为止,除DNM2外,还存在BIN1的未知伴侣,它们也参与了中央核肌病的发展。为了阐明这些其他相关的相互作用伙伴,并全面了解BIN1SH3域变体背后的病理机制,我们使用了亲和肌间技术。我们确定了数百个新的BIN1相互作用伙伴,其中许多似乎参与细胞分裂,提示BIN1在有丝分裂调节中的关键作用。最后,我们表明,确定的BIN1突变确实引起蛋白质组全亲和力扰动,表示采用无偏亲和力相互作用组学方法的重要性。
    Truncation of the protein-protein interaction SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1, Amphiphysin 2) protein leads to centronuclear myopathy. Here, we assessed the impact of a set of naturally observed, previously uncharacterized BIN1 SH3 domain variants using conventional in vitro and cell-based assays monitoring the BIN1 interaction with dynamin 2 (DNM2) and identified potentially harmful ones that can be also tentatively connected to neuromuscular disorders. However, SH3 domains are typically promiscuous and it is expected that other, so far unknown partners of BIN1 exist besides DNM2, that also participate in the development of centronuclear myopathy. In order to shed light on these other relevant interaction partners and to get a holistic picture of the pathomechanism behind BIN1 SH3 domain variants, we used affinity interactomics. We identified hundreds of new BIN1 interaction partners proteome-wide, among which many appear to participate in cell division, suggesting a critical role of BIN1 in the regulation of mitosis. Finally, we show that the identified BIN1 mutations indeed cause proteome-wide affinity perturbation, signifying the importance of employing unbiased affinity interactomic approaches.
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  • 文章类型: Journal Article
    Amphiphysin-2是一种广泛表达的蛋白质,也称为桥接整合因子1(BIN1)。在膜重塑中起关键作用,贩运,和广泛组织中的细胞骨架动力学。编码BIN1的基因突变导致核中央肌病(CNM),最近的证据表明BIN1与心力衰竭有关,强调其在骨骼肌和心肌中的关键作用。此外,BIN1表达的改变与晚发性阿尔茨海默病和几种癌症的风险增加有关,包括乳房,结肠,前列腺,和肺癌。最近,首次获得了调节BIN1治疗肌肉疾病的潜在治疗策略的概念验证.在这篇评论文章中,我们讨论了BIN1在心肌和骨骼肌中的功能的异同,与其相关的疾病和潜在的治疗方法。
    Amphiphysin-2 is a ubiquitously expressed protein also known as bridging integrator 1 (BIN1), playing a critical role in membrane remodeling, trafficking, and cytoskeleton dynamics in a wide range of tissues. Mutations in the gene encoding BIN1 cause centronuclear myopathies (CNM), and recent evidence has implicated BIN1 in heart failure, underlining its crucial role in both skeletal and cardiac muscle. Furthermore, altered expression of BIN1 is linked to an increased risk of late-onset Alzheimer\'s disease and several types of cancer, including breast, colon, prostate, and lung cancers. Recently, the first proof-of-concept for potential therapeutic strategies modulating BIN1 were obtained for muscle diseases. In this review article, we discuss the similarities and differences in BIN1\'s functions in cardiac and skeletal muscle, along with its associated diseases and potential therapies.
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  • 文章类型: Journal Article
    内吞作用是细胞营养物质内化所需的关键细胞途径,脂质和受体结合的货物。它对于细胞成分的回收也至关重要,细胞运输和膜动力学。通过重复的全基因组关联研究和内吞基因中罕见的编码突变的存在,内吞途径一直与阿尔茨海默病(AD)有关。BIN1和PICALM是APOE后两个最重要的迟发性AD风险基因,并且都是网格蛋白介导的内吞生物学的关键。病理学研究还表明,内吞功能障碍是晚发性AD的早期特征,在疾病的前驱阶段看到。大脑的不同细胞类型具有内吞途径的特定要求。神经元需要突触小泡的有效再循环,小胶质细胞使用内吞作用的特殊形式-吞噬作用-以实现其正常功能。因此,内吞基因的疾病相关变化将对不同细胞类型产生不同的影响,这还有待充分探索。鉴于AD中内吞功能障碍的遗传和病理证据,了解这些变化和相关的细胞类型特异性脆弱性如何影响正常细胞功能并导致疾病是至关重要的,并且可以提供新的治疗机会。本文是讨论会议议题“了解神经变性的内溶酶体网络”的一部分。
    Endocytosis is a key cellular pathway required for the internalization of cellular nutrients, lipids and receptor-bound cargoes. It is also critical for the recycling of cellular components, cellular trafficking and membrane dynamics. The endocytic pathway has been consistently implicated in Alzheimer\'s disease (AD) through repeated genome-wide association studies and the existence of rare coding mutations in endocytic genes. BIN1 and PICALM are two of the most significant late-onset AD risk genes after APOE and are both key to clathrin-mediated endocytic biology. Pathological studies also demonstrate that endocytic dysfunction is an early characteristic of late-onset AD, being seen in the prodromal phase of the disease. Different cell types of the brain have specific requirements of the endocytic pathway. Neurons require efficient recycling of synaptic vesicles and microglia use the specialized form of endocytosis-phagocytosis-for their normal function. Therefore, disease-associated changes in endocytic genes will have varied impacts across different cell types, which remains to be fully explored. Given the genetic and pathological evidence for endocytic dysfunction in AD, understanding how such changes and the related cell type-specific vulnerabilities impact normal cellular function and contribute to disease is vital and could present novel therapeutic opportunities. This article is part of a discussion meeting issue \'Understanding the endo-lysosomal network in neurodegeneration\'.
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  • 文章类型: Meta-Analysis
    路易体(LB)病理学通常发生在患有阿尔茨海默病(AD)病理学的个体中。然而,目前尚不清楚哪些遗传风险因素是AD病理的基础,LB病理学,或AD-LB共病。值得注意的是,APOE-ε4是否独立于AD病理影响LB病理的风险存在争议。我们调整了来自文献的标准,将来自国家阿尔茨海默病协调中心(NACC)和拉什大学医学中心的4,985名受试者分类为AD-LB共病(AD+LB+)。唯一的AD病理(AD+LB-),唯一的LB病理(AD-LB+),或无病理学(AD-LB-)。与对照组(AD-LB-)相比,我们对每个亚群(NACC/Rush)的每个疾病表型进行了全基因组关联研究(GWAS)的荟萃分析,并比较AD+LB+与AD+LB-组。与AD-LB-相比,APOE-ε4与AD+LB-和AD+LB+的风险显著相关。然而,与AD-LB-相比,APOE-ε4与AD-LB+的风险或与AD+LB+的风险无关。BIN1基因座处的关联显示出定性相似的结果。这些结果表明,APOE-ε4是AD病理的危险因素,但当与AD病理学分离时,不用于LB病理学。BIN1风险变体也是如此。这些发现,在迄今为止最大的AD-LB神经病理学GWAS中,区分单独和双重AD-LB病理表型的遗传风险因素.我们的GWAS荟萃分析汇总统计数据,来自基于死后病理评估的表型,与基于临床诊断的GWAS相比,可以提供更准确的疾病特异性多基因风险评分,这可能与未发现的痴呆型双重病理和临床误诊混淆。
    Lewy body (LB) pathology commonly occurs in individuals with Alzheimer\'s disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer\'s Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB-), sole LB pathology (AD-LB+), or no pathology (AD-LB-). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD-LB-), and compared the AD+LB+ to AD+LB- groups. APOE-ε4 was significantly associated with risk of AD+LB- and AD+LB+ compared to AD-LB-. However, APOE-ε4 was not associated with risk of AD-LB+ compared to AD-LB- or risk of AD+LB+ compared to AD+LB-. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.
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  • 文章类型: Journal Article
    更长的寿命会产生与年龄相关的神经退行性疾病的风险,如阿尔茨海默病(AD),其特征是记忆和认知功能下降。AD的致病原因被认为反映了由β-淀粉样蛋白(Aβ)肽组成的淀粉样蛋白斑块和由磷酸化tau蛋白组成的神经原纤维缠结在大脑中的逐渐聚集。最近,通过针对可溶性Aβ蛋白的被动免疫治疗,对Aβ疾病假说的长期研究获得了支持.使用抗体的Tau靶向方法也被追求作为AD的治疗方法。在全基因组关联研究中,疾病修饰基因Bin1已被确定为人群中晚发性AD的最高危险因素,最近的研究表明Bin1结合tau并影响其细胞外沉积。有趣的是,在AD出现在大脑之前,结肠中的tau水平上升,其中Bin1是组织屏障功能和炎症的调节剂,可促进炎症性肠病(IBD)。考虑到与年龄相关的神经退行性疾病中肠-脑通信的临床证据,这种联系具有挑衅性。包括AD。在这次审查中,我们讨论了我们实验室开发的用于治疗IBD的Bin1靶向被动免疫疗法,该疗法可能提供间接减少tau沉积并限制AD发病或进展的策略.
    Longer lifespan produces risks of age-associated neurodegenerative disorders such as Alzheimer\'s disease (AD), which is characterized by declines in memory and cognitive function. The pathogenic causes of AD are thought to reflect a progressive aggregation in the brain of amyloid plaques composed of beta-amyloid (Aß) peptides and neurofibrillary tangles composed of phosphorylated tau protein. Recently, long-standing investigations of the Aß disease hypothesis gained support via a passive immunotherapy targeting soluble Aß protein. Tau-targeting approaches using antibodies are also being pursued as a therapeutic approach to AD. In genome-wide association studies, the disease modifier gene Bin1 has been identified as a top risk factor for late-onset AD in human populations, with recent studies suggesting that Bin1 binds tau and influences its extracellular deposition. Interestingly, before AD emerges in the brain, tau levels rise in the colon, where Bin1-a modifier of tissue barrier function and inflammation-acts to promote inflammatory bowel disease (IBD). This connection is provocative given clinical evidence of gut-brain communication in age-associated neurodegenerative disorders, including AD. In this review, we discuss a Bin1-targeting passive immunotherapy developed in our laboratory to treat IBD that may offer a strategy to indirectly reduce tau deposition and limit AD onset or progression.
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  • 文章类型: Journal Article
    背景:在发育中的心脏中逐渐形成横向小管(t-小管),关键实现心肌细胞Ca2+稳态的成熟。膜弯曲和支架蛋白BIN1(两栖蛋白-2)参与了这一过程。然而,目前尚不清楚所报道的各种BIN1亚型涉及哪些,以及BIN1功能是否受其推定的结合伴侣MTM1(肌管蛋白)调节,磷酸肌醇3'-磷酸酶,和DNM2(dynamin-2),一种被认为介导膜裂变的GTP酶。
    方法:我们研究了BIN1,MTM1和DNM2在发育中的小鼠心肌细胞T管形成中的作用,以及基因修饰的HL-1和人诱导的多能干细胞衍生的心肌细胞。通过共聚焦和Airyscan显微镜对感兴趣的T小管和蛋白质进行成像,通过RT-qPCR和Western印迹检查表达模式。使用Fluo-4记录Ca2+释放。
    结果:我们观察到,在出生后的小鼠心脏中,BIN1从早期发育阶段沿Z线定位,与t小管初始萌芽和支架的作用一致。T管增殖和组织与4种检测到的BIN1亚型的逐步和平行增加有关。观察到所有同种型在心肌细胞中诱导管形,但产生具有不同几何形状的t-小管。BIN1诱导的管状包含L型Ca2通道,与caveolin-3和ryanodine受体共定位,并有效触发Ca2+释放。发育过程中BIN1的上调与MTM1表达的增加平行。尽管MTM1和小鼠心脏BIN1亚型之间没有直接结合,缺乏外显子11,高MTM1水平是BIN1诱导的插管所必需的,表明磷酸肌醇稳态的中心作用。相比之下,发育中的心脏显示DNM2水平下降。的确,我们观察到高水平的DNM2对t管形成有抑制作用,尽管这种蛋白质与BIN1沿Z线定位,并结合所有4种同工型。
    结论:这些发现表明,BIN1,MTM1和DNM2在控制心肌细胞t-小管生长方面具有平衡和协同作用。
    Transverse tubules (t-tubules) form gradually in the developing heart, critically enabling maturation of cardiomyocyte Ca2+ homeostasis. The membrane bending and scaffolding protein BIN1 (bridging integrator 1) has been implicated in this process. However, it is unclear which of the various reported BIN1 isoforms are involved, and whether BIN1 function is regulated by its putative binding partners MTM1 (myotubularin), a phosphoinositide 3\'-phosphatase, and DNM2 (dynamin-2), a GTPase believed to mediate membrane fission.
    We investigated the roles of BIN1, MTM1, and DNM2 in t-tubule formation in developing mouse cardiomyocytes, and in gene-modified HL-1 and human-induced pluripotent stem cell-derived cardiomyocytes. T-tubules and proteins of interest were imaged by confocal and Airyscan microscopy, and expression patterns were examined by RT-qPCR and Western blotting. Ca2+ release was recorded using Fluo-4.
    We observed that in the postnatal mouse heart, BIN1 localizes along Z-lines from early developmental stages, consistent with roles in initial budding and scaffolding of t-tubules. T-tubule proliferation and organization were linked to a progressive and parallel increase in 4 detected BIN1 isoforms. All isoforms were observed to induce tubulation in cardiomyocytes but produced t-tubules with differing geometries. BIN1-induced tubulations contained the L-type Ca2+ channel, were colocalized with caveolin-3 and the ryanodine receptor, and effectively triggered Ca2+ release. BIN1 upregulation during development was paralleled by increasing expression of MTM1. Despite no direct binding between MTM1 and murine cardiac BIN1 isoforms, which lack exon 11, high MTM1 levels were necessary for BIN1-induced tubulation, indicating a central role of phosphoinositide homeostasis. In contrast, the developing heart exhibited declining levels of DNM2. Indeed, we observed that high levels of DNM2 are inhibitory for t-tubule formation, although this protein colocalizes with BIN1 along Z-lines, and binds all 4 isoforms.
    These findings indicate that BIN1, MTM1, and DNM2 have balanced and collaborative roles in controlling t-tubule growth in cardiomyocytes.
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  • 文章类型: Journal Article
    人类诱导的多能干细胞衍生的心肌细胞(hiPSC-CM)在心脏再生医学中的未来用途在很大程度上取决于这些细胞的机电特性。特别是关于Ca2+依赖的激发-收缩(EC)耦合机制。目前,hiPSC-CM不成熟的结构和功能特征限制了其临床应用的进展.这里,我们表明,特定的微结构对于hiPSC-CM的功能成熟至关重要。向长方体细胞形状的结构重塑和BIN1的诱导,BIN1是膜内陷的促进剂,导致横向(t)管状结构。这种转变带来了两个对EC耦合至关重要的Ca2通道,肌膜上的L型Ca2通道和肌浆网上的ryanodine受体。因此,这些通道的Ca2+依赖性功能相互作用变得更有效,导致改进的Ca2+瞬变的时空同步和更高的EC耦合增益。因此,未来的心脏再生方法需要考虑通过优化的细胞微体系结构实现hiPSC心肌细胞的功能成熟。
    The prospective use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for cardiac regenerative medicine strongly depends on the electro-mechanical properties of these cells, especially regarding the Ca2+-dependent excitation-contraction (EC) coupling mechanism. Currently, the immature structural and functional features of hiPSC-CM limit the progression towards clinical applications. Here, we show that a specific microarchitecture is essential for functional maturation of hiPSC-CM. Structural remodelling towards a cuboid cell shape and induction of BIN1, a facilitator of membrane invaginations, lead to transverse (t)-tubule-like structures. This transformation brings two Ca2+ channels critical for EC coupling in close proximity, the L-type Ca2+ channel at the sarcolemma and the ryanodine receptor at the sarcoplasmic reticulum. Consequently, the Ca2+-dependent functional interaction of these channels becomes more efficient, leading to improved spatio-temporal synchronisation of Ca2+ transients and higher EC coupling gain. Thus, functional maturation of hiPSC-cardiomyocytes by optimised cell microarchitecture needs to be considered for future cardiac regenerative approaches.
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  • 文章类型: Journal Article
    常染色体显性多囊肾病(ADPKD)患者常出现心肌病,即使他们有正常的肾功能和动脉压。心肌细胞多囊素-1(PC1)在心血管病理生理学中的作用尚不清楚。PC1是保持T管结构的BIN1的潜在调节剂,和BIN1表达的改变诱导心脏病变。我们使用心肌细胞特异性PC1沉默(PC1-KO)小鼠模型来探索心肌细胞PC1在心力衰竭(HF)发展中的相关性。认为BIN1表达减少诱导T管重塑是一种潜在的机制。PC1-KO小鼠表现出心脏功能受损,通过超声心动图测量,但在7-9个月大之前没有HF的迹象。在PC1-KO小鼠中,43%的人在7个月大时突然死亡,9个月后100%死于扩张型心肌病。总BIN1mRNA,蛋白质水平,在PC1-KO小鼠中,其在富含质膜部分中的定位降低。此外,在没有HF迹象的小鼠中,BIN113同种型降低,而BIN11317同种型过表达。然而,在患有HF的小鼠中未观察到BIN1+13+17过表达。血浆样品中测量的T-小管重塑和BIN1评分与PC1-BIN1表达减少和HF发展相关。我们的结果表明,心肌细胞中PC1表达减少可诱导与BIN1表达减少和T管重塑相关的扩张型心肌病。总之,PC1对BIN1表达的正调节提示了一个新的通路,该通路可能与理解导致ADPKD患者心肌病的病理生理机制有关.
    Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7-9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients.
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