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Biol Psychiatry. 2018 Aug 25. pii: S0006-3223(18)31782-7. doi: 10.1016/j.biopsych.2018.08.009. [Epub ahead of print]

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

Author information

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.

KEYWORDS:

Alzheimer’s disease; PSD-93; PSD-95; RPS23RG1; Synaptic plasticity; Ubiquitination

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