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

  • Dongdong Zhao
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Jian Meng
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Yingjun Zhao
    Affiliations
    Neuroscience Initiative, Sanford–Burnham–Prebys Medical Discovery Institute, La Jolla, California
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  • Yuanhui Huo
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Yan Liu
    Affiliations
    Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen, Fujian, China

    Neuroscience Initiative, Sanford–Burnham–Prebys Medical Discovery Institute, La Jolla, California
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  • Naizhen Zheng
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Muxian Zhang
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Yue Gao
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Zhicai Chen
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Hao Sun
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Xiangyu Wang
    Affiliations
    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
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  • Chuya Jing
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Tongmei Zhang
    Affiliations
    Neuroscience Initiative, Sanford–Burnham–Prebys Medical Discovery Institute, La Jolla, California
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  • Xian Zhang
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Hong Luo
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Xin Wang
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Jie Zhang
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Fa-rong Liu
    Affiliations
    Department of Psychology, Xiamen Xianyue Hospital, Xiamen, Fujian, China
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  • Yanfang Li
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Guojun Bu
    Affiliations
    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
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  • Lei Wen
    Affiliations
    Department of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen, Fujian, China
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  • Timothy Y. Huang
    Affiliations
    Neuroscience Initiative, Sanford–Burnham–Prebys Medical Discovery Institute, La Jolla, California
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  • Author Footnotes
    1 HX and Y-wZ contributed equally to this work as senior authors.
    Huaxi Xu
    Footnotes
    1 HX and Y-wZ contributed equally to this work as senior authors.
    Affiliations
    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
    Search for articles by this author
  • Author Footnotes
    1 HX and Y-wZ contributed equally to this work as senior authors.
    Yun-wu Zhang
    Correspondence
    Address correspondence to Yun-wu Zhang, Ph.D., Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian 361102, China.
    Footnotes
    1 HX and Y-wZ contributed equally to this work as senior authors.
    Affiliations
    Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian, China
    Search for articles by this author
  • Author Footnotes
    1 HX and Y-wZ contributed equally to this work as senior authors.

      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

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