• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

两种TrkC受体亚型的矛盾信号为肌萎缩侧索硬化症新型治疗策略提供了理论依据。

The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS.

作者信息

Brahimi Fouad, Maira Mario, Barcelona Pablo F, Galan Alba, Aboulkassim Tahar, Teske Katrina, Rogers Mary-Louise, Bertram Lisa, Wang Jing, Yousefi Masoud, Rush Robert, Fabian Marc, Cashman Neil, Saragovi H Uri

机构信息

Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.

Flinders University, Department of Human Physiology, Centre for Neuroscience, Adelaide, Australia.

出版信息

PLoS One. 2016 Oct 3;11(10):e0162307. doi: 10.1371/journal.pone.0162307. eCollection 2016.

DOI:10.1371/journal.pone.0162307
PMID:27695040
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5047590/
Abstract

Full length TrkC (TrkC-FL) is a receptor tyrosine kinase whose mRNA can be spliced to a truncated TrkC.T1 isoform lacking the kinase domain. Neurotrophin-3 (NT-3) activates TrkC-FL to maintain motor neuron health and function and TrkC.T1 to produce neurotoxic TNF-α; hence resulting in opposing pathways. In mouse and human ALS spinal cord, the reduction of miR-128 that destabilizes TrkC.T1 mRNA results in up-regulated TrkC.T1 and TNF-α in astrocytes. We exploited conformational differences to develop an agonistic mAb 2B7 that selectively activates TrkC-FL, to circumvent TrkC.T1 activation. In mouse ALS, 2B7 activates spinal cord TrkC-FL signals, improves spinal cord motor neuron phenotype and function, and significantly prolongs life-span. Our results elucidate biological paradoxes of receptor isoforms and their role in disease progression, validate the concept of selectively targeting conformational epitopes in naturally occurring isoforms, and may guide the development of pro-neuroprotective (TrkC-FL) and anti-neurotoxic (TrkC.T1) therapeutic strategies.

摘要

全长TrkC（TrkC-FL）是一种受体酪氨酸激酶，其信使核糖核酸（mRNA）可剪接成缺少激酶结构域的截短型TrkC.T1亚型。神经营养因子-3（NT-3）激活TrkC-FL以维持运动神经元的健康和功能，激活TrkC.T1以产生神经毒性肿瘤坏死因子-α（TNF-α）；因此导致相反的信号通路。在小鼠和人类肌萎缩侧索硬化症（ALS）脊髓中，使TrkC.T1 mRNA不稳定的微小核糖核酸-128（miR-128）减少，导致星形胶质细胞中TrkC.T1和TNF-α上调。我们利用构象差异开发了一种激动性单克隆抗体2B7，它能选择性激活TrkC-FL，从而规避TrkC.T1的激活。在小鼠ALS模型中，2B7激活脊髓TrkC-FL信号，改善脊髓运动神经元表型和功能，并显著延长寿命。我们的研究结果阐明了受体亚型的生物学悖论及其在疾病进展中的作用，验证了选择性靶向天然存在亚型中构象表位的概念，并可能指导促神经保护（TrkC-FL）和抗神经毒性（TrkC.T1）治疗策略的开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/a7618d556f26/pone.0162307.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/4defe5790666/pone.0162307.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/b6df4c9ea9d8/pone.0162307.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/728d70673222/pone.0162307.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/cf71705f511a/pone.0162307.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/0ca3c4acfd66/pone.0162307.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/c284596ac244/pone.0162307.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/a7618d556f26/pone.0162307.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/4defe5790666/pone.0162307.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/b6df4c9ea9d8/pone.0162307.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/728d70673222/pone.0162307.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/cf71705f511a/pone.0162307.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/0ca3c4acfd66/pone.0162307.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/c284596ac244/pone.0162307.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e0a/5047590/a7618d556f26/pone.0162307.g007.jpg

相似文献

1
The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS.两种TrkC受体亚型的矛盾信号为肌萎缩侧索硬化症新型治疗策略提供了理论依据。
PLoS One. 2016 Oct 3;11(10):e0162307. doi: 10.1371/journal.pone.0162307. eCollection 2016.
2
In glaucoma the upregulated truncated TrkC.T1 receptor isoform in glia causes increased TNF-alpha production, leading to retinal ganglion cell death.在青光眼患者中，胶质细胞中上调的截断型 TrkC.T1 受体同工型导致 TNF-α 产生增加，从而导致视网膜神经节细胞死亡。
Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6639-51. doi: 10.1167/iovs.10-5431. Epub 2010 Jun 23.
3
Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation.Sigma-1 受体激动剂 PRE-084 在非 SOD1 突变相关运动神经元疾病小鼠模型中的神经保护作用。
Neurobiol Dis. 2014 Feb;62:218-32. doi: 10.1016/j.nbd.2013.10.010. Epub 2013 Oct 16.
4
An agonistic mAb directed to the TrkC receptor juxtamembrane region defines a trophic hot spot and interactions with p75 coreceptors.一种针对 TrkC 受体跨膜区的激动型单克隆抗体定义了一个营养热点，并与 p75 核心受体相互作用。
Dev Neurobiol. 2010 Feb 15;70(3):150-64. doi: 10.1002/dneu.20776.
5
Activation of mGlu3 metabotropic glutamate receptors enhances GDNF and GLT-1 formation in the spinal cord and rescues motor neurons in the SOD-1 mouse model of amyotrophic lateral sclerosis.mGlu3 代谢型谷氨酸受体的激活增强了脊髓中的 GDNF 和 GLT-1 的形成，并挽救了 SOD-1 肌萎缩侧索硬化症小鼠模型中的运动神经元。
Neurobiol Dis. 2015 Feb;74:126-36. doi: 10.1016/j.nbd.2014.11.012. Epub 2014 Nov 28.
6
Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.胍那苄可延缓疾病症状的出现，延长寿命，改善运动能力，并减轻肌萎缩侧索硬化症SOD1 G93A小鼠模型中的运动神经元损失。
Neuroscience. 2014 Sep 26;277:132-8. doi: 10.1016/j.neuroscience.2014.03.047. Epub 2014 Mar 31.
7
Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor.干扰素-β通过上调截短型TrkC-T1受体的表达来抑制神经营养因子3信号传导和促生存活性。
Mol Neurobiol. 2017 Apr;54(3):1825-1843. doi: 10.1007/s12035-016-9789-2. Epub 2016 Feb 18.
8
Neuroprotective effects of JGK-263 in transgenic SOD1-G93A mice of amyotrophic lateral sclerosis.JGK-263对肌萎缩侧索硬化转基因SOD1-G93A小鼠的神经保护作用。
J Neurol Sci. 2014 May 15;340(1-2):112-6. doi: 10.1016/j.jns.2014.03.008. Epub 2014 Mar 12.
9
Differential effects of TrkC isoforms on sensory axon outgrowth.TrkC 亚型对感觉轴突生长的不同影响。
J Neurosci Res. 2000 Feb 1;59(3):365-71. doi: 10.1002/(sici)1097-4547(20000201)59:3<365::aid-jnr10>3.0.co;2-i.
10
Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis.抑制腺苷2a受体（A2aR）介导的腺苷信号传导可改善肌萎缩侧索硬化小鼠模型的疾病表型。
Exp Neurol. 2015 May;267:115-22. doi: 10.1016/j.expneurol.2015.03.004. Epub 2015 Mar 13.

引用本文的文献

1
Selective inhibitors of the TrkC.T1 receptor reduce retinal inflammation and delay neuronal death in a model of retinitis pigmentosa.在视网膜色素变性模型中，TrkC.T1受体的选择性抑制剂可减轻视网膜炎症并延缓神经元死亡。
PNAS Nexus. 2025 Feb 4;4(2):pgaf020. doi: 10.1093/pnasnexus/pgaf020. eCollection 2025 Feb.
2
Srsf1 and Elavl1 act antagonistically on neuronal fate choice in the developing neocortex by controlling TrkC receptor isoform expression.Srsf1和Elavl1通过控制TrkC受体亚型的表达，在发育中的新皮质神经元命运选择中发挥拮抗作用。
Nucleic Acids Res. 2023 Oct 27;51(19):10218-10237. doi: 10.1093/nar/gkad703.
3
MicroRNA Alteration, Application as Biomarkers, and Therapeutic Approaches in Neurodegenerative Diseases.

本文引用的文献

1
Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm.神经营养因子受体激动剂和拮抗剂作为治疗药物：一个不断发展的范例。
Neurobiol Dis. 2017 Jan;97(Pt B):139-155. doi: 10.1016/j.nbd.2016.08.004. Epub 2016 Aug 18.
2
A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo.一种前神经生长因子（proNGF）和神经生长因子结合蛋白α2-巨球蛋白对p75和TrkA受体具有不同的调节作用，且与体内外神经退行性变相关。
Mol Cell Biol. 2015 Oct;35(19):3396-408. doi: 10.1128/MCB.00544-15. Epub 2015 Jul 27.
3
微小 RNA 改变、作为生物标志物的应用及在神经退行性疾病中的治疗方法。
Int J Mol Sci. 2022 Apr 25;23(9):4718. doi: 10.3390/ijms23094718.
4
Human-Induced Pluripotent Stem Cell-Based Models for Studying Sex-Specific Differences in Neurodegenerative Diseases.基于人诱导多能干细胞的神经退行性疾病性别差异研究模型。
Adv Exp Med Biol. 2022;1387:57-88. doi: 10.1007/5584_2021_683.
5
Intranasal delivery of exosomes from human adipose derived stem cells at forty-eight hours post injury reduces motor and cognitive impairments following traumatic brain injury.在创伤性脑损伤后48小时经鼻递送源自人脂肪干细胞的外泌体可减轻运动和认知障碍。
Neurochem Int. 2021 Nov;150:105173. doi: 10.1016/j.neuint.2021.105173. Epub 2021 Aug 25.
6
Neuroprotection: Pro-survival and Anti-neurotoxic Mechanisms as Therapeutic Strategies in Neurodegeneration.神经保护：促生存和抗神经毒性机制作为神经退行性疾病的治疗策略
Front Cell Neurosci. 2019 Jun 6;13:231. doi: 10.3389/fncel.2019.00231. eCollection 2019.
7
Neuron-targeted caveolin-1 improves neuromuscular function and extends survival in SOD1 mice.神经元靶向窖蛋白-1改善 SOD1 小鼠的神经肌肉功能并延长其生存时间。
FASEB J. 2019 Jun;33(6):7545-7554. doi: 10.1096/fj.201802652RR. Epub 2019 Mar 20.
8
The effects of neuregulin-1β on intrafusal muscle fiber formation in neuromuscular coculture of dorsal root ganglion explants and skeletal muscle cells.神经调节蛋白-1β对背根神经节外植体和骨骼肌细胞神经肌肉共培养中肌梭内肌纤维形成的影响。
Skelet Muscle. 2018 Sep 15;8(1):29. doi: 10.1186/s13395-018-0175-9.
9
CRISPR/Cas9 nickase mediated targeting of urokinase receptor gene inhibits neuroblastoma cell proliferation.CRISPR/Cas9切口酶介导的尿激酶受体基因靶向作用抑制神经母细胞瘤细胞增殖。
Oncotarget. 2018 Jun 29;9(50):29414-29430. doi: 10.18632/oncotarget.25647.
10
In retinitis pigmentosa TrkC.T1-dependent vectorial Erk activity upregulates glial TNF-α, causing selective neuronal death.在色素性视网膜炎中，TrkC.T1 依赖性载体 Erk 活性上调胶质细胞 TNF-α，导致选择性神经元死亡。
Cell Death Dis. 2017 Dec 14;8(12):3222. doi: 10.1038/s41419-017-0074-8.
Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis.
突触形成过程中细胞外顺式和反式RPTPσ信号竞争的结构基础。
Nat Commun. 2014 Nov 11;5:5209. doi: 10.1038/ncomms6209.
4
The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis.神经营养因子受体p75的细胞外结构域作为肌萎缩侧索硬化症的候选生物标志物。
PLoS One. 2014 Jan 27;9(1):e87398. doi: 10.1371/journal.pone.0087398. eCollection 2014.
5
A multifunctional neurotrophin with reduced affinity to p75NTR enhances transplanted Schwann cell survival and axon growth after spinal cord injury.一种多功能神经营养因子，对 p75NTR 的亲和力降低，可增强脊髓损伤后移植雪旺细胞的存活和轴突生长。
Exp Neurol. 2013 Oct;248:170-82. doi: 10.1016/j.expneurol.2013.06.013. Epub 2013 Jun 20.
6
Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.BDNF 截断受体 TrkB.T1 的缺失可延迟肌萎缩侧索硬化症小鼠模型的疾病发作。
PLoS One. 2012;7(6):e39946. doi: 10.1371/journal.pone.0039946. Epub 2012 Jun 27.
7
Translating the therapeutic potential of neurotrophic factors to clinical 'proof of concept': a personal saga achieving a career-long quest.将神经营养因子的治疗潜力转化为临床“概念验证”：实现毕生追求的个人传奇。
Neurobiol Dis. 2012 Nov;48(2):153-78. doi: 10.1016/j.nbd.2012.04.004. Epub 2012 Apr 16.
8
p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity.p75 神经营养因子受体信号在神经系统损伤和变性中的作用：矛盾与机遇。
Trends Neurosci. 2012 Jul;35(7):431-40. doi: 10.1016/j.tins.2012.03.007. Epub 2012 Apr 13.
9
Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.人运动神经元祖细胞移植导致 3 种运动神经元丢失模型中的内源性神经元保留。
Stem Cells Int. 2011;2011:207230. doi: 10.4061/2011/207230. Epub 2011 May 23.
10
Ligand-dependent TrkA activity in brain differentially affects spatial learning and long-term memory.脑内配体依赖性 TrkA 活性对空间学习和长期记忆有不同影响。
Mol Pharmacol. 2011 Sep;80(3):498-508. doi: 10.1124/mol.111.071332. Epub 2011 May 26.