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Roles of UBE3A-mediated p18 regulation in synaptogenesis and synaptic plasticity

UBE3A 介导的 p18 调节在突触发生和突触可塑性中的作用

基本信息

批准号：
10356151
负责人：
MICHEL BAUDRY
金额：
$ 30.84万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356151
关键词：
Actins Acylation Adult Affect Amino Acids Angelman Syndrome Binding Brain CDK6-associated protein p18 Cell Line Cells Complex Dendritic Spines Development Excision FRAP1 gene Glycine Hippocampus (Brain)Impairment In Vitro Learning Light Link Long-Term Potentiation Lysosomes Mediating Membrane Memory Morphology Motor Mus N-terminal Neurodevelopmental Disorder Neurons Play Process Regulation Reporting Research Risk Role Signal Pathway Signal Transduction Sirolimus Site Slice Social Interaction Synapses Synaptic plasticity System Testing UBE3A gene Ubiquitin Ubiquitination Vertebral column Visual Cortex autism spectrum disorder calmodulin-dependent protein kinase II dimer experience in vivo interdisciplinary approach knock-down member mouse model multicatalytic endopeptidase complex myristoylation nervous system disorder neurobiological mechanism neuropsychiatric disorder new therapeutic target novel overexpression palmitoylation polymerization recruit synaptogenesis ubiquitin-protein ligase

项目摘要

UBE3A, an E3 ligase in the ubiquitin-proteasomal system, plays important roles in brain development and function. Optimal CNS UBE3A expression is crucial since its deficiency results in Angelman syndrome (AS), while its over- expression increases the risk for autism. Yet, the precise function of UBE3A in the CNS remains largely unknown. In AS mouse models, Ube3a deficiency leads to deficits in motor function, learning and memory, and social interactions. We have recently reported that Ube3a deficiency leads to increased activation of mTORC1 but decreased activation of mTORC2, the two core complexes in the mechanistic target of rapamycin (mTOR) signaling pathway. However, how UBE3A deficiency results in mTORC1 over-activation remains unknown. Emerging evidence indicates that the presence of amino acids is essential for full mTORC1 activation. Amino acid-induced mTORC1 activation depends on the recruitment of mTORC1 to late endosomal/lysosomal membranes, a process involving the formation of heterodimers of a RagA or RagB, with a RagC or RagD through binding to the Ragulator. The anchoring of Ragulator to lysosomal membrane is through one of its components, p18. Myristoylation and palmitoylation in the N-terminal domain of p18 are critical for its lysosomal localization. Our preliminary results revealed that p18 levels were increased as a result of Ube3a deficiency in COS1 cells and in AS mouse brain. We further showed that p18 could be ubiquitinated by Ube3a in COS1 cells. These findings led us to propose the central hypothesis that, under normal conditions, lysosomal localized p18 levels are controlled by Ube3a-mediated ubiquitination, which targets p18 for proteasomal degradation. A correlate of this hypothesis is that lack of Ube3a-mediated p18 ubiquitination and degradation in AS mice results in imbalanced mTORC1/mTORC2 signaling and abnormal spine morphology and synaptic plasticity. We will first identify the ubiquitination sites in p18 and determine whether N-terminal acylation affects Ube3a- mediated p18 ubiquitination. We will then determine whether Ube3a-mediated p18 regulation plays important roles in synaptogenesis, synaptic plasticity, and experience-dependent remodeling of synapses using a multidisciplinary approach. Since both UBE3A deficiency and overexpression are linked to neurodevelopmental disorders, understanding UBE3A-mediated regulation of p18 and of mTOR signaling and its role in synaptogenesis and synaptic plasticity should shed light on basic neurobiological mechanisms, as well as on several neurological and neuropsychiatric diseases.

UBE 3A是泛素-蛋白酶体系统中的一种E3连接酶，在脑发育和功能中起重要作用。最佳CNS UBE 3A表达是至关重要的，因为它的缺陷导致Angelman综合征（AS），而它的过度表达则导致AS。表达会增加患自闭症的风险。然而，UBE 3A在CNS中的确切功能在很大程度上仍然未知。在AS小鼠模型中，Ube 3a缺乏导致运动功能、学习和记忆以及社交功能的缺陷。交互.我们最近报道，Ube 3a缺陷导致mTORC 1激活增加，降低mTORC 2的激活，这是雷帕霉素（mTOR）机制靶点中的两个核心复合物信号通路然而，UBE 3A缺陷如何导致mTORC 1过度激活仍然未知。新出现的证据表明，氨基酸的存在对于mTORC 1的完全激活至关重要。氨基酸诱导的mTORC 1活化依赖于mTORC 1向晚期内体/溶酶体的募集，膜，涉及RagA或RagB与RagC或RagD的异二聚体形成的过程通过绑定到Ragulator。Ragulator与溶酶体膜的锚定是通过其组件，第18页。p18蛋白N-末端结构域的肉豆蔻酰化和棕榈酰化是其表达的关键。溶酶体定位我们的初步结果表明，p18水平的增加是由于Ube 3a COS 1细胞和AS小鼠脑中的缺陷。我们进一步表明，p18可以被Ube 3a泛素化， COS 1细胞。这些发现使我们提出了一个中心假设，即在正常条件下，定位的p18水平由Ube 3a介导的泛素化控制，其靶向p18蛋白酶体，降解这一假说的一个相关性是，AS中缺乏Ube 3a介导的p18泛素化和降解，小鼠导致不平衡的mTORC 1/mTORC 2信号传导和异常的脊柱形态和突触可塑性。我们将首先确定p18中的泛素化位点，并确定N-末端酰化是否影响Ube 3a。介导的p18泛素化。然后我们将确定Ube 3a介导的p18调控是否在在突触发生、突触可塑性和经验依赖性突触重塑中的作用，多学科方法。由于UBE 3A缺陷和过度表达都与神经发育障碍，了解UBE 3A介导的p18和mTOR信号转导的调节，它在突触发生和突触可塑性中的作用应该阐明基本的神经生物学机制，以及几种神经和神经精神疾病。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer's Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain.

Capn1 基因的缺失会导致与阿尔茨海默病、蛋白质质量控制和小鼠大脑突触可塑性相关的信号通路发生改变。

DOI：
10.3389/fgene.2020.00334
发表时间：
2020
期刊：
Frontiers in genetics
影响因子：
3.7
作者：
Su,Wenyue;Zhou,Qian;Wang,Yubin;Chishti,Athar;Li,QingshunQ;Dayal,Sujay;Shiehzadegan,Shayan;Cheng,Ariel;Moore,Clare;Bi,Xiaoning;Baudry,Michel
通讯作者：
Baudry,Michel

UBE3A deficiency-induced autophagy is associated with activation of AMPK-ULK1 and p53 pathways.

UBE3A 缺陷诱导的自噬与 AMPK-ULK1 和 p53 通路的激活相关。

DOI：
10.1016/j.expneurol.2023.114358
发表时间：
2023
期刊：
Experimental neurology
影响因子：
5.3
作者：
Hao,Xiaoning;Sun,Jiandong;Zhong,Li;Baudry,Michel;Bi,Xiaoning
通讯作者：
Bi,Xiaoning

SK2 channel regulation of neuronal excitability, synaptic transmission, and brain rhythmic activity in health and diseases.

DOI：
10.1016/j.bbamcr.2020.118834
发表时间：
2020-12
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
0
作者：
Sun J;Liu Y;Baudry M;Bi X
通讯作者：
Bi X

LAMTOR1 inhibition of TRPML1-dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function.

DOI：
10.15252/embj.2021108119
发表时间：
2022-03-01
期刊：
The EMBO journal
影响因子：
0
作者：
Sun J;Liu Y;Hao X;Lin W;Su W;Chiang E;Baudry M;Bi X
通讯作者：
Bi X

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity.

UBE3A 介导的 p18/LAMTOR1 泛素化和降解调节 mTORC1 活性和突触可塑性。

DOI：
10.7554/elife.37993
发表时间：
2018
期刊：
eLife
影响因子：
7.7
作者：
Sun,Jiandong;Liu,Yan;Jia,Yousheng;Hao,Xiaoning;Lin,WeiJu;Tran,Jennifer;Lynch,Gary;Baudry,Michel;Bi,Xiaoning
通讯作者：
Bi,Xiaoning