Impairment of TrkB-PSD-95 signaling in Angelman syndrome.
Impairment of TrkB-PSD-95 signaling in Angelman syndrome.
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DOI：
10.1371/journal.pbio.1001478
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Marshall J
中科院分区：
文献类型：
--
作者：
Cao C;Rioult-Pedotti MS;Migani P;Yu CJ;Tiwari R;Parang K;Spaller MR;Goebel DJ;Marshall J
脑源性神经营养因子信号传导在Angelman综合征中是有缺陷的，可以通过破坏Arc/PSD 95结合来挽救。Angelman综合征（AS）是一种以严重的认知功能障碍和高孤独症发生率为特征的神经发育障碍。AS是由母体遗传的Ube 3A泛素蛋白连接酶的神经元表达中断引起的，该蛋白连接酶是突触可塑性中涉及的蛋白质的蛋白酶体降解所必需的，例如活性调节的细胞内相关蛋白（Arc/Arg3.1）。缺乏母体Ube 3A的小鼠表达水平升高的Arc以响应突触活动，这与海马中严重受损的长时程增强（LTP）和学习行为的缺陷相一致。在这项研究中，我们试图测试Arc水平升高是否会干扰脑源性神经营养因子（BDNF）TrkB受体信号传导，这是已知的诱导和维持LTP所必需的。我们报告AS小鼠中的TrkB信号传导存在缺陷，并表明Arc表达降低至控制水平可以挽救信号传导缺陷。此外，突触后密度蛋白PSD-95与TrkB的关联对于完整的BDNF信号传导是至关重要的，并且发现Arc水平升高会阻碍PSD-95/TrkB的关联。在Ube 3A缺陷小鼠中，BDNF诱导的PSD-95以及PLCγ和Grb 2相关结合物1（Gab 1）与TrkB受体的募集减弱，导致PLCγ-α-钙/钙调素依赖性蛋白激酶II（CaMKII）和PI 3 K-Akt的活化减少，但细胞外信号调节激酶（Erk）通路保持完整。核磁共振（NMR）研究表明，一种桥环肽（CN 2097）以高亲和力独特地结合PSD-95的PDZ 1结构域，降低了Arc与PSD-95的相互作用，以恢复BDNF诱导的TrkB/PSD-95复合物形成、信号传导，并促进AS小鼠中LTP的诱导。我们提出，AS中突触处TrkB受体信号传导的失败与PSD-95和PSD-95 PDZ配体相关的Arc水平升高直接相关，这可能代表了逆转认知功能障碍的有希望的方法。Angelman综合征（AS）是一种由Ube 3A基因功能障碍引起的衰弱性神经系统疾病。大多数患有AS的儿童表现出发育迟缓、运动障碍、言语障碍，并且通常具有自闭症特征。Ube 3A酶通常调节突触蛋白Arc的降解，并且在其缺乏的情况下，所产生的Arc水平升高会削弱突触接触，使得难以产生长时程增强（LTP）以及处理和储存记忆。在这项研究中，我们发现Arc水平的增加通过TrkB受体破坏脑源性神经营养因子（BDNF）信号传导（这对LTP的诱导和维持都很重要）。我们发现，突触后密度蛋白PSD-95与TrkB的关联对于完整的BDNF信号传导是至关重要的，并且AS中高水平的Arc干扰BDNF诱导的突触后密度蛋白95（PSD-95）和其他效应物对TrkB的募集。通过用新型环状肽模拟物化合物CN 2097破坏Arc和PSD-95之间的相互作用，我们能够恢复BDNF信号传导并改善AS小鼠模型中LTP的诱导。我们认为TrkB受体信号在突触处的中断有助于Angelman综合征中发生的认知功能障碍。
Brain-derived neurotrophic factor signaling is defective in Angelman syndrome and can be rescued by disruption of Arc/PSD95 binding. Angelman syndrome (AS) is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP) in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF) TrkB receptor signaling, which is known to be essential for both the induction and maintenance of LTP. We report that TrkB signaling in the AS mouse is defective, and show that reduction of Arc expression to control levels rescues the signaling deficits. Moreover, the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and elevated levels of Arc were found to impede PSD-95/TrkB association. In Ube3A deficient mice, the BDNF-induced recruitment of PSD-95, as well as PLCγ and Grb2-associated binder 1 (Gab1) with TrkB receptors was attenuated, resulting in reduced activation of PLCγ-α-calcium/calmodulin-dependent protein kinase II (CaMKII) and PI3K-Akt, but leaving the extracellular signal-regulated kinase (Erk) pathway intact. A bridged cyclic peptide (CN2097), shown by nuclear magnetic resonance (NMR) studies to uniquely bind the PDZ1 domain of PSD-95 with high affinity, decreased the interaction of Arc with PSD-95 to restore BDNF-induced TrkB/PSD-95 complex formation, signaling, and facilitate the induction of LTP in AS mice. We propose that the failure of TrkB receptor signaling at synapses in AS is directly linked to elevated levels of Arc associated with PSD-95 and PSD-95 PDZ-ligands may represent a promising approach to reverse cognitive dysfunction. Angelman syndrome (AS) is a debilitating neurological disorder caused by a dysfunctional Ube3A gene. Most children with AS exhibit developmental delay, movement disorders, speech impairment, and often autistic features. The Ube3A enzyme normally regulates the degradation of the synaptic protein Arc, and in its absence the resulting elevated levels of Arc weaken synaptic contacts, making it difficult to generate long-term potentiation (LTP) and to process and store memory. In this study, we show that increased levels of Arc disrupt brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor (which is important for both the induction and maintenance of LTP). We find that the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and that the high levels of Arc in AS interfere with BDNF-induced recruitment of postsynaptic density protein-95 (PSD-95) and other effectors to TrkB. By disrupting the interaction between Arc and PSD-95 with the novel cyclic peptidomimetic compound CN2097, we were able to restore BDNF signaling and improve the induction of LTP in a mouse model of AS. We propose that the disruption of TrkB receptor signaling at synapses contributes to the cognitive dysfunction that occurs in Angelman syndrome.
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DOI：
10.1083/jcb.150.6.1423
发表时间：
2000-09-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Du J;Feng L;Yang F;Lu B
通讯作者：
Lu B
影响因子：
16.2
作者：
Chowdhury, Shoaib;Shepherd, Jason D.;Worley, Paul F.
通讯作者：
Worley, Paul F.
影响因子：
64.8
作者：
Huang, Hsien-Sung;Allen, John A.;Mabb, Angela M.;King, Ian F.;Miriyala, Jayalakshmi;Taylor-Blake, Bonnie;Sciaky, Noah;Dutton, J. Walter, Jr.;Lee, Hyeong-Min;Chen, Xin;Jin, Jian;Bridges, Arlene S.;Zylka, Mark J.;Roth, Bryan L.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.
影响因子：
16.2
作者：
Elias, Guillermo M.;Funke, Lars;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.
影响因子：
9.9
作者：
Fernandez, Esperanza;Collins, Mark O.;Uren, Rachel T.;Kopanitsa, Maksym V.;Komiyama, Noboru H.;Croning, Mike D. R.;Zografos, Lysimachos;Armstrong, J. Douglas;Choudhary, Jyoti S.;Grant, Seth G. N.
通讯作者：
Grant, Seth G. N.