RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits

Dongdong Zhao; Jian Meng; Yingjun Zhao; Yuanhui Huo; Yan Liu; Naizhen Zheng; Muxian Zhang; Yue Gao; Zhicai Chen; Hao Sun; Xiangyu Wang; C. Jing; Tongmei Zhang; Xian Zhang; Hong Luo; Xin Wang; Jie Zhang; Fa rong Liu; Yanfang Li; Guojun Bu; Lei Wen; Timothy Y. Huang; H. Xu; Yun wu Zhang

doi:10.1016/j.biopsych.2018.08.009

RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits

Dongdong Zhao, Jian Meng, Yingjun Zhao, Yuanhui Huo, Yan Liu, Naizhen Zheng, Muxian Zhang, Yue Gao, Zhicai Chen, Hao Sun, Xiangyu Wang, C. Jing, Tongmei Zhang, Xian Zhang, Hong Luo, Xin Wang, Jie Zhang, Fa rong Liu, Yanfang Li, Guojun BuLei Wen, Timothy Y. Huang, H. Xu, Yun wu Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

30 Citations (Scopus)

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.

Original language	English
Pages (from-to)	171-184
Number of pages	14
Journal	Biological Psychiatry
Volume	86
Issue number	3
DOIs	https://doi.org/10.1016/j.biopsych.2018.08.009
Publication status	Published - 1 Aug 2019
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2018 Society of Biological Psychiatry

Keywords

Alzheimer's disease
PSD-93
PSD-95
RPS23RG1
Synaptic plasticity
Ubiquitination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.biopsych.2018.08.009

Cite this

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, F. R., Li, Y., ... Zhang, Y. W. (2019). RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits. Biological Psychiatry, 86(3), 171-184. https://doi.org/10.1016/j.biopsych.2018.08.009

@article{376e2c81b9b846cfa987a3348d44081d,

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 = "Publisher Copyright: {\textcopyright} 2018 Society of Biological Psychiatry",

year = "2019",

month = aug,

day = "1",

doi = "10.1016/j.biopsych.2018.08.009",

language = "English",

volume = "86",

pages = "171--184",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "3",

}

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 2019, 'RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits', Biological Psychiatry, vol. 86, no. 3, pp. 171-184. https://doi.org/10.1016/j.biopsych.2018.08.009

TY - JOUR

T1 - RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits

AU - Zhao, Dongdong

AU - Meng, Jian

AU - Zhao, Yingjun

AU - Huo, Yuanhui

AU - Liu, Yan

AU - Zheng, Naizhen

AU - Zhang, Muxian

AU - Gao, Yue

AU - Chen, Zhicai

AU - Sun, Hao

AU - Wang, Xiangyu

AU - Jing, C.

AU - Zhang, Tongmei

AU - Zhang, Xian

AU - Luo, Hong

AU - Wang, Xin

AU - Zhang, Jie

AU - Liu, Fa rong

AU - Li, Yanfang

AU - Bu, Guojun

AU - Wen, Lei

AU - Huang, Timothy Y.

AU - Xu, H.

AU - Zhang, Yun wu

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - PSD-93

KW - PSD-95

KW - RPS23RG1

KW - Synaptic plasticity

KW - Ubiquitination

UR - https://www.webofscience.com/wos/woscc/full-record/WOS:000475424100005

UR - https://openalex.org/W2888322964

UR - https://www.scopus.com/pages/publications/85054144620

U2 - 10.1016/j.biopsych.2018.08.009

DO - 10.1016/j.biopsych.2018.08.009

M3 - Journal Article

C2 - 30292394

SN - 0006-3223

VL - 86

SP - 171

EP - 184

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 3

ER -

RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease–Associated Cognitive Deficits

Abstract

Bibliographical note

Keywords

UN SDGs

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