@article{b2db7b21e77743ea8912fbd629b04575,
title = "RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits",
abstract = "Background: Although synaptic impairment is a 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. Methods: 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 pathways has therapeutic potential in APP/PS1 AD model mice. Results: Deletion of the Rps23rg1 gene resulted in severe memory deficits and impairment of postsynaptic structure and function, with marked reductions in postsynaptic densities-93 and -95 (PSD-93 and PSD-95) levels. RPS23RG1 interacted with PSD-93/PSD-95 through its intracellular domain, consequently sequestering PSD-93/PSD-95 from murine double minute 2–mediated ubiquitination and degradation, thereby maintaining synaptic function. Restoration of PSD-93/PS-D95 levels reversed synaptic and memory deficits in Rps23rg1 knockout 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 knockout and AD mouse models. Conclusions: 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.",
keywords = "Alzheimer's disease, PSD-93, PSD-95, RPS23RG1, Synaptic plasticity, Ubiquitination",
author = "Dongdong Zhao and Jian Meng and Yingjun Zhao and Yuanhui Huo and Yan Liu and Naizhen Zheng and Muxian Zhang and Yue Gao and Zhicai Chen and Hao Sun and Xiangyu Wang and C. Jing and Tongmei Zhang and Xian Zhang and Hong Luo and Xin Wang and Jie Zhang and Liu, {Fa rong} and Yanfang Li and Guojun Bu and Lei Wen and Huang, {Timothy Y.} and H. Xu and Zhang, {Yun wu}",
note = "Funding Information: This work was supported in part by grants from the National Key Research and Development Program of China (Grant No. 2016YFC1305903 [to Y-wZ]), the National Natural Science Foundation of China (Grant Nos. 91332112 , U1705285 , 81225008 , and 81771377 to [Y-wZ], Grant No. U1405222 [to HX], and Grant Nos. 81774377 and 81373999 to [LW]), the National Institutes of Health (Grant Nos. R01AG021173 , R01AG038710 , R01AG044420 , and R01NS046673 [to HX]), Fundamental Research Funds for the Central Universities (Grant No. 20720180049 [to Y-wZ]), the Xiamen Science and Technology Program for Public Wellbeing (Grant No. 3502Z20174067 to [F-rL]), and the Natural Science Foundation of Guangdong Province of China (Grant No. 2018A030313158 [to YLi]). Funding Information: This work was supported in part by grants from the National Key Research and Development Program of China (Grant No. 2016YFC1305903 [to Y-wZ]), the National Natural Science Foundation of China (Grant Nos. 91332112, U1705285, 81225008, and 81771377 to [Y-wZ], Grant No. U1405222 [to HX], and Grant Nos. 81774377 and 81373999 to [LW]), the National Institutes of Health (Grant Nos. R01AG021173, R01AG038710, R01AG044420, and R01NS046673 [to HX]), Fundamental Research Funds for the Central Universities (Grant No. 20720180049 [to Y-wZ]), the Xiamen Science and Technology Program for Public Wellbeing (Grant No. 3502Z20174067 to [F-rL]), and the Natural Science Foundation of Guangdong Province of China (Grant No. 2018A030313158 [to YLi]). Publisher Copyright: {\textcopyright} 2018 Society of Biological Psychiatry",
year = "2019",
month = aug,
day = "1",
doi = "10.1016/j.biopsych.2018.08.009",
language = "English (US)",
volume = "86",
pages = "171--184",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "3",
}