更新于：2024-11-01

ELP1

更新于：2024-11-01

基本信息

别名

DYS、elongator acetyltransferase complex subunit 1、Elongator complex protein 1

+ [8]

简介

Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:29332244). Regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation (By similarity). ELP1 binds to tRNA, mediating interaction of the elongator complex with tRNA (By similarity). May act as a scaffold protein that assembles active IKK-MAP3K14 complexes (IKKA, IKKB and MAP3K14/NIK) (PubMed:9751059).

关联

项与 ELP1 相关的药物

PTC-0405403

靶点

ELP1 x splicing factor

作用机制

ELP1基因调节剂 [+1]

在研机构

PTC Therapeutics, Inc. [+2]

原研机构

The General Hospital Corp.

在研适应症

家族性自主神经功能异常

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 ELP1 相关的临床结果

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100 项与 ELP1 相关的转化医学

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0 项与 ELP1 相关的专利（医药）

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372

项与 ELP1 相关的文献（医药）

2024-09-11·The Journal of Neuroscience

ELP1, the Gene Mutated in Familial Dysautonomia, Is Required for Normal Enteric Nervous System Development and Maintenance and for Gut Epithelium Homeostasis

Article

作者: Kaufmann, Horacio ; Henningsen, Katelyn ; Chaverra, Marta ; George, Lynn ; Miller, Alessa ; Walk, Seth ; Scheel, Alpha ; Cheney, Alexandra M ; Schultz, Anastasia ; Kominsky, Douglas ; Lefcort, Frances ; Kennedy, William R ; Copié, Valérie ; Walk, Heather

Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in theELP1gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only isElp1required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in whichElp1was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion ofElp1exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis.

2024-09-01·Neurobiology of Disease

Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia

Article

作者: Joshi, Piyush ; Ahmad, Shiekh Tanveer ; Radoš, Magdalena ; Northcott, Paul A ; Li, Yiran ; Kutscher, Lena M ; Spänig, Lisa ; Bianchini, Luca ; Schouw, Mackenna E ; Patrizi, Annarita ; Lin, Hong ; Lukasch, Chiara ; Garcia-Lopez, Jesus ; Sepp, Mari ; Roiuk, Mykola ; da Silva, Patricia Benites Goncalves ; Arnskötter, Frederik ; Sieber, Laura ; Zuckermann, Marc

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1^cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1^cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

2024-07-10·Histology and histopathology

Brain endothelial cell activation and dysfunction associate with and contribute to the development of enlarged perivascular spaces and cerebral small vessel disease.

Review

作者: Hayden, Melvin Ray

Multiple injurious stimuli to the brain's endothelium results in brain endothelial cell activation and dysfunction (BECact/dys) with upregulation of inflammatory signaling cascades and a decrease in bioavailable nitric oxide respectively. These injurious stimuli initiate a brain injury and a response to injury wound healing genetically programed cascade of events, which result in cellular remodeling of the neurovascular unit and blood-brain barrier with increased inflammation and permeability. These remodeling changes also include the perivascular spaces that become dilated to form enlarged perivascular spaces (EPVS) that may be identified noninvasively by magnetic resonance imaging. These EPVS are associated with and considered to be a biomarker for cerebral small vessel disease (SVD) and a dysfunctional glymphatic system with impaired removal of neurotoxic waste, which ultimately results in neurodegeneration with impaired cognition and dementia. The penultimate section discusses the understudied role of venous cerebral circulation in relation to EPVS, SVD, and the vascular contribution to cognitive impairment (VCID). The focus of this review will be primarily on BECact/dys that associates with and contributes to the development of EPVS, SVD, and impaired glymphatic system efflux. Importantly, BECact/dys may be a key piece of the puzzle to unlock this complicated story of EPVS and SVD. Multiple transmission electron micrographs and illustrations will be utilized to depict anatomical ultrastructure and allow for the discussion of multiple functional molecular cascades.

项与 ELP1 相关的新闻（医药）

2024-01-26

·生物探索

Science | 闫建斌/雷晓光破解紫杉醇生物合成的难题

引言紫杉醇是一种众所周知的抗癌化合物。它的生物合成包括形成一个高度功能化的二萜核心骨架(baccatin III)和随后的苯基异丝氨酸侧链的组装。尽管经过半个世纪的深入研究，baccatin III的完整生物合成途径仍然未知。2024年1月25日，中国农业科学院农业基因组研究所闫建斌及北京大学雷晓光共同通讯在Science 在线发表题为”Characterization and heterologous reconstitution of Taxus biosynthetic enzymes leading to baccatin III“的研究论文，该研究发现了一种双功能细胞色素P450酶(Taxane oxetanase, TOT)，它催化紫杉醇oxetane形成中的氧化重排，代表了以前未知的oxetane环形成的酶机制。该研究建立了基于紫杉素（taxusin）生物合成途径的筛选策略，并发现了负责紫杉烷氧化C9位置(T9αH)的酶。最后，该研究在烟草中人工重组了一种生产baccatin III的生物合成途径。总之，该研究成功鉴定了紫杉醇生物途径的关键缺失酶，揭示了红豆杉催化含氧四元环分子形成的全新机制，发现了紫杉醇异源生物合成的核心基因，实现了紫杉醇核心前体baccatin III在烟草中的异源合成。该研究成果解决了紫杉醇生物合成研究中的关键瓶颈问题，是植物天然产物生物合成领域中的重大突破，为通过合成生物学的手段实现紫杉醇的高效、可持续生产铺平了道路，具有极高的科学创新性与应用价值。紫杉醇来源于红豆杉科红豆杉属植物的次生代谢，已被临床用于治疗多种癌症。紫杉醇含有结构复杂的6-8-6三环碳骨架，包含9个立体中心，1个显著的氧烷环基序和1个苯异丝氨酸链。紫杉醇可以穿过微管壁的纳米孔，与微管管腔表面的微管蛋白相互作用，破坏微管动力学，从而触发对癌细胞的细胞毒性作用。三环碳骨架的整体构象硬化是由紫杉醇的氧烷环产生的。目前用于生产紫杉醇的一种策略是化学半合成，即从植物细胞培养物或红豆杉的原始树木生物量中分离出紫杉醇前体，如baccatin III，然后化学转化为紫杉醇。这种半合成策略严重依赖自然资源和红豆杉植物的人工种植，无法满足日益增长的市场需求。以绿色和可持续的方式生产紫杉醇的生物合成策略已经变得非常有吸引力。在红豆杉植物中，TOT1负责氧乙烷的形成（Credit: Science ）自1971年首次发现紫杉醇结构以来，阐明其生物合成途径一直是天然产物研究中的一个具有挑战性的任务。迄今为止，大约有20种可能的酶促反应被报道。反应步骤可分为三个关键过程，包括从底物香叶基焦磷酸(GGPP)形成4(20)-烯-5α-醇片段的紫杉烷骨架，通过C4和C20双键的环氧化生物合成baccatin III，以及将苯基异丝氨酸链连接到baccatin III的C13位置生成紫杉醇。C13侧链的形成及其与baccatin III结合生成紫杉醇的研究已经得到了很好的研究。然而，形成baccatin III的几个基本步骤仍然未知，特别是氧烷环的形成和C9的氧化。因此，紫杉醇生物合成的上游和下游步骤无法连接，迄今为止缺乏完整的紫杉醇生物合成途径。该研究发现了一种双功能细胞色素P450酶(Taxane oxetanase, TOT)，它催化紫杉醇oxetane形成中的氧化重排，代表了以前未知的oxetane环形成的酶机制。该研究建立了基于紫杉素（taxusin）生物合成途径的筛选策略，并发现了负责紫杉烷氧化C9位置(T9αH)的酶。最后，该研究在烟草中人工重组了一种生产baccatin III的生物合成途径。5α-乙酰基4,20烯在TOT1介导的氧乙烷生成反应中是不可缺少的（Credit: Science ）原文链接https://www.science.org/doi/10.1126/science.adj3484责编|探索君排版|探索君文章来源|“iNature”End往期精选围观Nat Med | 黄荷凤院士/张静澜/徐晨明团队发表综合性无创产前筛查临床研究成果热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文Nat Methods | 自主生物发光成像技术在真核生物中的创新进展

临床3期