RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease-Associated Cognitive Deficits.
RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease-Associated Cognitive Deficits.
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RPS23RG1 是突触完整性所必需的，可挽救阿尔茨海默病相关的认知缺陷
DOI：
10.1016/j.biopsych.2018.08.009
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发表时间：
2019-08-01
影响因子：
10.6
通讯作者：
Zhang YW
中科院分区：
文献类型：
--
作者：
Zhao D;Meng J;Zhao Y;Huo Y;Liu Y;Zheng N;Zhang M;Gao Y;Chen Z;Sun H;Wang X;Jing C;Zhang T;Zhang X;Luo H;Wang X;Zhang J;Liu FR;Li Y;Bu G;Wen L;Huang TY;Xu H;Zhang YW
虽然突触损伤是阿尔茨海默病(AD)认知缺陷的先决条件，但基本突触支架成分及其完整性调节失调的机制仍然难以捉摸。RPS23RG1是一个新发现的与AD相关的蛋白。然而，RPS23RG1的生理功能尚未确定。我们研究了RPS23RG1在细胞培养和Rps23Rg1基因敲除小鼠中维持突触结构和功能的作用，并确定了靶向RPS23RG1介导的通路在APP/PS1 AD模型小鼠中是否具有治疗潜力。Rps23rg1基因缺失导致严重的记忆缺陷和突触后结构和功能的损害，PSD-93和PSD-95水平显著降低。RPS23RG1通过其胞内区与PSD-93/PSD-95相互作用，从而将PSD-93/PSD-95与MDM2介导的泛素化和降解隔离开来，从而维持突触功能。PSD-93/PSD95水平的恢复逆转了Rps23rg1KO小鼠的突触和记忆缺陷。我们进一步观察到RPS23RG1在人类AD中的表达减弱，这与PSD-93/PSD-95水平呈正相关。重要的是，含有独特的PSD-93/PSD-95相互作用基序的RPS23RG1衍生多肽挽救了Rps23Rg1 KO和AD小鼠模型中的突触和认知缺陷。我们的结果揭示了RPS23RG1在维持突触完整性和功能方面的作用，并为突触功能障碍在AD发病中的作用提供了新的机制。这表明RPS23RG1介导的通路在AD干预中显示出良好的治疗潜力。
Although synaptic impairment is prerequisite to cognitive deficiencies in Alzheimer’s disease (AD), mechanisms underlying the dysregulation of essential synaptic scaffolding components and their integrity remain elusive. RPS23RG1 is a newly identified protein implicated in AD. However, the physiological function of RPS23RG1 has yet to be determined. We investigated the role of RPS23RG1 in maintaining synaptic structure and function in cell cultures and in Rps23rg1 knockout mice, and determined whether targeting RPS23RG1-mediated pathway has therapeutic potential in APP/PS1 AD model mice. Deletion of the Rps23rg1 gene resulted in severe memory deficits and impairment of post-synaptic structure and function, with marked reductions in PSD-93 and PSD-95 levels. RPS23RG1 interacted with PSD-93/PSD-95 through its intracellular domain, consequently sequestering PSD-93/PSD-95 from MDM2-mediated ubiquitination and degradation, thereby maintaining synaptic function. Restoration of PSD-93/PSD95 levels reversed synaptic and memory deficits in Rps23rg1 KO mice. We further observed attenuated RPS23RG1 expression in human AD, which positively correlated with PSD-93/PSD-95 levels. Importantly, an RPS23RG1-derived peptide comprising a unique PSD-93/PSD-95 interaction motif rescued synaptic and cognitive defects in Rps23rg1 KO and AD mouse models. Our results reveal a role for RPS23RG1 in maintaining synaptic integrity and function and provide a new mechanism for synaptic dysfunction in AD pathogenesis. This demonstrates that RPS23RG1-mediated pathways show good therapeutic potential in AD intervention.
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影响因子：
3.5
作者：
Huang, Xiumei;Chen, Yaomin;Zhang, Yun-wu
通讯作者：
Zhang, Yun-wu
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：
4.7
作者：
Dakoji, S;Tomita, S;Bredt, DS
通讯作者：
Bredt, DS
影响因子：
6.1
作者：
Almeida, CG;Tampellini, D;Gouras, GK
通讯作者：
Gouras, GK
DOI：
10.1073/pnas.1517045112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Chen, Xiaobing;Levy, Jonathan M.;Reese, Thomas S.
通讯作者：
Reese, Thomas S.