Dongdong Zhao1, Jian Meng1, Yingjun Zhao2, Yuanhui Huo1, Yan Liu3, Naizhen Zheng1, Muxian Zhang1, Yue Gao1, Zhicai Chen1, Hao Sun1, Xiangyu Wang4, Chuya Jing1, Tongmei Zhang2, Xian Zhang1, Hong Luo1, Xin Wang1, Jie Zhang1, Fa-Rong Liu5, Yanfang Li1, Guojun Bu6, Lei Wen7, Timothy Y Huang2, Huaxi Xu8, Yun-Wu Zhang9. 1. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China. 2. Neuroscience Initiative, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California. 3. Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen, Fujian, China; Neuroscience Initiative, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California. 4. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China. 5. Department of Psychology, Xiamen Xianyue Hospital, Xiamen, Fujian, China. 6. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida. 7. Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen, Fujian, China. 8. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China; Neuroscience Initiative, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California. 9. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China. Electronic address: yunzhang@xmu.edu.cn.
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.
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.
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