Branding/Logomark minus Citation Combined Shape Icon/Bookmark-empty Icon/Copy Icon/Collection Icon/Close Copy 7 no author result Created with Sketch. Icon/Back Created with Sketch. Match!

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

Published on Aug 1, 2018in Biological Psychiatry 11.50
· 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)
Cite
Abstract
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.
  • References (56)
  • Citations (2)
Cite
References56
Newest
Published on May 1, 2018in Molecular Psychiatry 11.97
D C Ung1
Estimated H-index: 1
,
Giovanni Iacono8
Estimated H-index: 8
+ 23 AuthorsStéphane Martin24
Estimated H-index: 24
Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X...
Published on Dec 1, 2017in Brain 11.81
Fernando J. Bustos7
Estimated H-index: 7
(Andrés Bello National University),
Estibaliz Ampuero4
Estimated H-index: 4
(Andrés Bello National University)
+ 19 AuthorsBerta Henriquez10
Estimated H-index: 10
(Andrés Bello National University)
The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer’s disease and Huntington’s disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigeneti...
Published on Dec 1, 2017in Nature Communications 11.88
Michelle L. Krishnan10
Estimated H-index: 10
(St Thomas' Hospital),
Juliette Van Steenwinckel14
Estimated H-index: 14
(Paris Diderot University)
+ 18 AuthorsConstance Auvynet13
Estimated H-index: 13
(UPMC: Pierre-and-Marie-Curie University)
Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial tr...
Published on Aug 1, 2017in Molecular Neurobiology 4.59
Qiuyang Zheng6
Estimated H-index: 6
(Ha Tai: Xiamen University),
Xiaoyuan Zheng3
Estimated H-index: 3
(Ha Tai: Xiamen University)
+ 11 AuthorsJian Meng1
Estimated H-index: 1
(Ha Tai: Xiamen University)
TMEM59L is a newly identified brain-specific membrane-anchored protein with unknown functions. Herein we found that both TMEM59L and its homolog, TMEM59, are localized in Golgi and endosomes. However, in contrast to a ubiquitous and relatively stable temporal expression of TMEM59, TMEM59L expression was limited in neurons and increased during development. We also found that both TMEM59L and TMEM59 interacted with ATG5 and ATG16L1, and that overexpression of them triggered cell autophagy. However...
Published on Jul 29, 2017in Journal of Alzheimer's Disease 3.70
Linjie Yu9
Estimated H-index: 9
,
Yi Liu3
Estimated H-index: 3
+ 5 AuthorsYun Xu24
Estimated H-index: 24
Published on Apr 1, 2017in Molecular Neurobiology 4.59
Daniela Vallejo2
Estimated H-index: 2
(UC: Pontifical Catholic University of Chile),
Juan Francisco Codocedo8
Estimated H-index: 8
(UC: Pontifical Catholic University of Chile),
Nibaldo C. Inestrosa64
Estimated H-index: 64
(UNSW: University of New South Wales)
The postsynaptic density (PSD) consists of a lattice-like array of interacting proteins that organizes and stabilizes synaptic receptors, ion channels, structural proteins, and signaling molecules required for normal synaptic transmission and synaptic function. The scaffolding and hub protein postsynaptic density protein-95 (PSD-95) is a major element of central chemical synapses and interacts with glutamate receptors, cell adhesion molecules, and cytoskeletal elements. In fact, PSD-95 can regul...
Published on Dec 1, 2016in Molecular Neurodegeneration 8.27
Mickael Audrain2
Estimated H-index: 2
(Paris V: Paris Descartes University),
Romain Fol4
Estimated H-index: 4
(Paris V: Paris Descartes University)
+ 12 AuthorsAlexis-Pierre Bemelmans17
Estimated H-index: 17
(Université Paris-Saclay)
Background Alzheimer’s disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction...
Published on Jun 1, 2016in Embo Molecular Medicine 10.62
Dennis J. Selkoe161
Estimated H-index: 161
(Brigham and Women's Hospital),
John Hardy149
Estimated H-index: 149
(UCL Institute of Neurology)
Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protei...
Published on Jun 1, 2016in Alzheimers & Dementia 14.42
David Hondius3
Estimated H-index: 3
(VU: VU University Amsterdam),
Pim van Nierop13
Estimated H-index: 13
(VU: VU University Amsterdam)
+ 6 AuthorsAugust B. Smit63
Estimated H-index: 63
(VU: VU University Amsterdam)
Abstract Introduction We performed a comprehensive quantitative proteomics study on human hippocampus tissue involving all Braak stages to assess changes in protein abundance over the various stages of Alzheimer's disease (AD). Methods Hippocampal subareas CA1 and subiculum of 40 cases were isolated using laser capture microdissection and analyzed using mass spectrometry. Immunoblotting and immunohistochemistry were used for validation. Results Over the Braak stages, an altered expression was fo...
Published on May 1, 2016in Scientific Reports 4.01
Li Yan2
Estimated H-index: 2
,
Yaomin Chen10
Estimated H-index: 10
+ 11 AuthorsLimin Li3
Estimated H-index: 3
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and is characterized pathologically by the extracellular deposition of β-amyloid (Aβ) peptides and intracellular tangles comprising phosphorylated tau proteins1,2. Soluble oligomeric Aβ species are believed to cause synaptic and neuronal loss in AD, and their expression in AD-affected regions correlates with the severity of premortem dementia more closely than the presence of insoluble Aβ plaques3,4,5. Aβ peptides vary i...
Cited By2
Newest
Published on Aug 1, 2019in Biological Psychiatry 11.50
Katherine R. Sadleir8
Estimated H-index: 8
(NU: Northwestern University),
Robert Vassar51
Estimated H-index: 51
(NU: Northwestern University)
Published on Feb 6, 2019in Frontiers in Neurology 2.63
Yuhai Zhao25
Estimated H-index: 25
(LSU Health Sciences Center New Orleans),
Vivian Jaber3
Estimated H-index: 3
(LSU Health Sciences Center New Orleans)
+ 2 AuthorsWalter J. Lukiw49
Estimated H-index: 49
(LSU Health Sciences Center New Orleans)
Integrating a combination of bioinformatics, microRNA microfluidic arrays, ELISA analysis, LED Northern and transfection-luciferase reporter assay data using human neuronal-glial (HNG) cells in primary culture we have discovered a set of up-regulated microRNAs (miRNAs) linked to a small family of down-regulated messenger RNAs (mRNAs) within the superior temporal lobe neocortex (Brodman A22) of sporadic Alzheimer’s disease (AD) brain. At the level of mRNA abundance, the expression of a significan...