更新于：2024-11-01

AGRN

更新于：2024-11-01

基本信息

别名

agrin、Agrin C-terminal 110 kDa subunit、Agrin C-terminal 22 kDa fragment

+ [5]

简介

Heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms. Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation. This released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia. Is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity).

关联

项与 AGRN 相关的药物

NT-1640

靶点

AGRN x LRP4

作用机制

AGRN stimulators [+1]

在研机构

Neurotune AG

原研机构

Neurotune AG

在研适应症

肌肉减少症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 AGRN 相关的临床结果

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100 项与 AGRN 相关的转化医学

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0 项与 AGRN 相关的专利（医药）

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1,357

项与 AGRN 相关的文献（医药）

2024-11-01·Journal of Neuroimmunology

Elevated serum levels of C-terminal agrin fragment in acetylcholine receptor antibody-positive myasthenia gravis

Article

作者: Masuda, Hiroki ; Handa, Hideo ; Uzawa, Akiyuki ; Onishi, Yosuke ; Ogaya, Etsuko ; Ozawa, Yukiko ; Kuwabara, Satoshi ; Mori, Masahiro ; Akamine, Hiroyuki ; Yasuda, Manato

Agrin is essential for neuromuscular junction (NMJ) formation and maintenance. The C-terminal agrin fragment (CAF), generated by neurotrypsin-mediated cleavage of agrin, has been gaining attention as a potential biomarker for sarcopenia. We investigated serum CAF levels in myasthenia gravis (MG), a NMJ disorder. Compared to healthy controls, serum CAF levels were significantly elevated in acetylcholine receptor antibody-positive MG (AChR-MG) patients, but not in muscle-specific kinase antibody-positive MG patients. In AChR-MG, baseline and post-treatment CAF levels inversely correlated with post-treatment MG activities of daily living scores, suggesting that elevated CAF levels may reflect protective mechanisms against AChR-MG pathogenesis, such as improved NMJ regeneration.

2024-10-01·Biochemical and Biophysical Research Communications

A class of chemical compounds enhances clustering of muscle nicotinic acetylcholine receptor in cultured myogenic cells

Article

作者: Tomita, Hiroyuki ; Sawada, Ryusuke ; Nakashima, Hiroaki ; Masuda, Akio ; Ohno, Kinji ; Hosono, Yasuyuki ; Imagama, Shiro ; Miyairi, Yuichi ; Sato, Ayato ; Ito, Mikako ; Ishii, Hisao ; Inoue, Taro ; Ohkawara, Bisei

Neuromuscular signal transmission is affected in various diseases including myasthenia gravis, congenital myasthenic syndromes, and sarcopenia. We used an ATF2-luciferase system to monitor the phosphorylation of MuSK in HEK293 cells introduced with MUSK and LRP4 cDNAs to find novel chemical compounds that enhanced agrin-mediated acetylcholine receptor (AChR) clustering. Four compounds with similar chemical structures carrying benzene rings and heterocyclic rings increased the luciferase activities 8- to 30-folds, and two of them showed continuously graded dose dependence. The effects were higher than that of disulfiram, a clinically available aldehyde dehydrogenase inhibitor, which we identified to be the most competent preapproved drug to enhance ATF2-luciferase activity in the same assay system. In C2C12 myotubes, all the compounds increased the area, intensity, length, and number of AChR clusters. Three of the four compounds increased the phosphorylation of MuSK, but not of Dok7, JNK. ERK, or p38. Monitoring cell toxicity using the neurite elongation of NSC34 neuronal cells as a surrogate marker showed that all the compounds had no effects on the neurite elongation up to 1 μM. Extensive docking simulation and binding structure prediction of the four compounds with all available human proteins using AutoDock Vina and DiffDock showed that the four compounds were unlikely to directly bind to MuSK or Dok7, and the exact target remained unknown. The identified compounds are expected to serve as a seed to develop a novel therapeutic agent to treat defective NMJ signal transmission.

2024-09-24·Proceedings of the National Academy of Sciences

Agonist antibody to MuSK protects mice from MuSK myasthenia gravis

Article

作者: Oury, Julien ; Burden, Steven J. ; Steyaert, Christophe ; Vankerckhoven, Bernhardt ; Silence, Karen ; Mar, Adam C. ; Vergoossen, Dana L. E. ; Santana, Leah ; Gamallo-Lana, Begona ; Huijbers, Maartje G. ; Vanhauwaert, Roeland

Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.

项与 AGRN 相关的新闻（医药）

2023-09-24

·佰傲谷BioValley

7种神经系统自免疾病

在中枢神经系统（CNS）、周围神经系统（PNS）也存在靶向自身抗原的抗体，通过引起异常免疫反应导致神经性自身免疫性疾病（NAD）发生。主要免疫病理机制与针对神经系统表达的抗原的适应性免疫反应相关，不同病理生理学机制与NAD相关。明确疾病背后的免疫机制是创造更具体治疗方法的重要前提。多发性硬化症（MS）MS是最常见的CNS脱髓鞘疾病，主要在大脑白质束、视神经、髓鞘处存在炎症病变。发生CNS内/外的损伤造成CNS抗原暴露，通过激活异常自身免疫反应使髓鞘受损。APC（巨噬、DC）将抗原吞噬并激活B、T细胞，其中Th1、Th17释放多种促炎白介素引发炎症并向CNS募集其他免疫细胞，CD8+T细胞通过HLA-Ⅰ识别神经元细胞肽，通过细胞毒性作用导致细胞死亡。并且在随后的疾病进展过程中，因髓鞘受损，轴突再生只有星形胶质细胞参与而无髓磷脂。Sciencedirect视神经脊髓炎（NMO）NMO包括横贯性脊髓炎（TM）和急性视神经脊髓炎，主要与水通道蛋白4的自身抗体（AQP4-IgG）相关，各类病毒（CMV、HSV、EBV、ZKV）被确定为NMO的潜在触发因素。感染情况下大脑中CSF、CXCL13、BAFF水平升高，激活B、浆细胞产生AQP4抗体。抗体的存在与视神经炎（ON）患者发生躯干脊髓炎、脑炎有关，并且抗体浓度患者伴有广泛脑损伤、完全失明、急性发作。AQP4-IgG通过Fc段激活补体后还继续激活中性粒（分泌弹性蛋白酶）、嗜酸性粒细胞（产生IL-4），介导炎症发生。格林巴利综合症（GBS）GBS是一种急性炎症性多发性神经根病，主要表现上行性肌无力。全身感染或其他因素诱发的先天免疫反应激活后，引发针对PNS神经根轴突或髓磷脂层的适应性免疫反应，导致急性轴突损伤或髓磷脂快速剥脱。位于轴突细胞膜的神经节苷脂是体液免疫（Ig）的主要目标，导致膜攻击复合物形成和轴突附近巨噬细胞募集来自神经内膜的巨噬细胞是疾病发生中的主角，在被补体激活后：吞噬髓磷脂、轴突成分，产生多种促炎细胞因子（IL-1、IL-12、TNFα）激活浆细胞（产生抗体）和T细胞（产生TNFα和IFNγ）；在TNFα刺激下转化为促炎表型，共同介导疾病的炎症过程。Sciencedirect慢性炎症性脱髓鞘性多发性神经病（CIDP）CIDP是一种炎症性多发性神经病，也以脱髓鞘为特征。主要诱发因素也是感染（细菌、病毒），相关的免疫反应发生在周围神经和脊髓根部。浸润的巨噬、T细胞会导致脱髓鞘和轴突变性，并产生IFNγ、TNFα、IL-2介导炎症发生。巨噬细胞参与脱髓鞘的最后部分；CD4+T细胞会改变BBB，促进粘附分子、IL表达；CD8+T细胞通过细胞毒性作用介导损伤。重症肌无力（MG）MG患者在神经肌肉接头存在AchR和突触后膜相关分子抗体，因信号被阻断导致全身肌肉无力，特别是眼部。这类抗体产生的免疫病理机制尚不完全明确，目前只观察到80%患者有胸腺滤泡增生、10%患者有胸腺瘤。胸腺增生造成GC中B细胞数量增加，而这在正常胸腺中不常见。过量产生的B细胞是抗AchR抗体的来源，也说明针对AchR的耐受性丧失发生胸腺中。并且胸腺中自身反应性T细胞增加也是导致疾病发生的原因，这些T细胞针对肌肉抗原。与MG相关的抗原可分为细胞内抗原和细胞外抗原。抗原‍抗体，作用机制胞外AchR激活补体；阻断Ach结合位点。MuSK屏蔽LRP4和ColQ的结合位点。LRP4激活补体；干扰Agrin和LRP4的结合。Agrin影响MuSK磷酸化，阻止AchR聚集。Colq-Kv1.4-胞内肌动蛋白结合在明暗带之间。兰尼定受体-皮质素-Sciencedirect自身免疫性脑炎（AIE）AIE是由自身免疫引起的脑部疾病，抗体针对细胞内/表面分子。诱因包括感染（主要是HSV）和癌症（主因），且有40%-50%患者病因不明。若是神经系统感染所致，损伤会激活免疫系统识别的抗原，产生异常免疫反应。根据抗体类型也分两类：神经元细胞外抗原抗体，IgG沉积物导致可逆性神经元损伤，中度炎症水平。神经元细胞内抗原抗体，抗体不能被内化，由CTL介导广泛损伤、高水平炎症。胞外抗原N-甲基-D-天冬氨酸受体，AIE的主要原因。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸，多种胸部肿瘤副肿瘤综合征相关。γ-氨基丁酸A/B受体。甘氨酸受体。代谢性谷氨酸受体1/5。腺苷酸激酶5。Ig样细胞粘附分子5（IgLON5）。胞内抗原谷氨酸脱羧酶65，80%T1D患者。大脑中B细胞激活、克隆扩增、成熟，产生的抗体激活补体、NK的细胞杀伤途径，导致细胞死亡。副肿瘤性神经系统疾病（PND）PND发生与肿瘤中存在的神经元蛋白有关。这类蛋白在肿瘤凋亡时释放，被APC摄取并携带至淋巴结递呈给CD4+T细胞然后激活B细胞，B细胞再次接触抗原时分化浆细胞并产生抗体。PND受累部位主要在CNS，肺癌、乳腺癌、淋巴瘤、胃肠道肿瘤依次是PND最常见诱因。PND与AIE相关，针对胞外抗原的抗体会引起AIE，针对胞内抗原则通过CD8+T细胞造成不可逆损伤。Sciencedirect小结这类疾病的治疗采取了多种方法，包括静脉注射Ig、B细胞耗竭、拮抗细胞因子、化疗，但疗效并不统一。未来研究可能在针对遗传、表观遗传学的方向中会为患者带来更具体、更加个性化的治疗方案。参考资料https://www.sciencedirect.com/science/article/pii/B9780323950619000333Acosta-Ampudia Y, Monsalve DM, Ramírez-Santana C. Identifying the culprits in neurological autoimmune diseases [published correction appears in J Transl Autoimmun. 2020 Feb 25;3:100041]. J Transl Autoimmun. 2019;2:100015. Published 2019 Sep 6. doi:10.1016/j.jtauto.2019.100015Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15. doi:10.1111/j.1365-2249.2008.03834.xDarnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003;349(16):1543-1554. doi:10.1056/NEJMra023009本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ ···

免疫疗法临床研究