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

Published on Aug 1, 2018in Biological Psychiatry11.50
· DOI :10.1016/j.biopsych.2018.08.009
Dongdong Zhao1
Estimated H-index: 1
(Ha Tai: Xiamen University),
Jian Meng1
Estimated H-index: 1
(Ha Tai: Xiamen University)
+ 21 AuthorsYun Wu Zhang21
Estimated H-index: 21
(Ha Tai: Xiamen University)
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.
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#1Fernando J. Bustos (Andrés Bello National University)H-Index: 7
#2Estibaliz Ampuero (Andrés Bello National University)H-Index: 4
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