Please use this identifier to cite or link to this item: https://doi.org/10.1111/acel.12551
Title: TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
Authors: Husain N. 
Yuan Q. 
Yen Y.-C. 
Pletnikova O.
Sally D.Q.
Worley P.
Bichler Z. 
Shawn Je H. 
Keywords: activity regulated cytoskeleton associated protein
AMPA receptor
protein
RNF216 protein
TRIAD3 protein
unclassified drug
activity regulated cytoskeletal-associated protein
AMPA receptor
clathrin
cytoskeleton protein
gonadorelin
nerve protein
protein binding
RNF216 protein, mouse
ubiquitin protein ligase
animal cell
animal experiment
Article
brain cell
carboxy terminal sequence
cognitive defect
comparative study
controlled study
COS-7 cell line
degenerative disease
dorsal hippocampus
gene overexpression
genetic association
genetic variability
gordon holmes syndrome
hippocampal CA1 region
hippocampal neuronal culture
loss of function mutation
male
missense mutation
molecular weight
mouse
nerve cell plasticity
nonhuman
nonsense mutation
priority journal
protein degradation
protein expression
rat
spatial learning
synapse
synaptic transmission
ubiquitination
upregulation
animal
C57BL mouse
cerebellar ataxia
cognitive defect
deficiency
endocytosis
gene silencing
genetics
HEK293 cell line
human
hypogonadism
metabolism
missense mutation
mutation
pathology
spatial memory
Sprague Dawley rat
synaptic transmission
Animals
CA1 Region, Hippocampal
Cerebellar Ataxia
Clathrin
Cognitive Dysfunction
Cytoskeletal Proteins
Endocytosis
Gene Knockdown Techniques
Gonadotropin-Releasing Hormone
HEK293 Cells
Humans
Hypogonadism
Mice, Inbred C57BL
Mutation
Mutation, Missense
Nerve Tissue Proteins
Protein Binding
Proteolysis
Rats, Sprague-Dawley
Receptors, AMPA
Spatial Memory
Synapses
Synaptic Transmission
Ubiquitin-Protein Ligases
Ubiquitination
Issue Date: 2017
Publisher: Blackwell Publishing Ltd
Citation: Husain N., Yuan Q., Yen Y.-C., Pletnikova O., Sally D.Q., Worley P., Bichler Z., Shawn Je H. (2017). TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. Aging Cell 16 (2) : 281-292. ScholarBank@NUS Repository. https://doi.org/10.1111/acel.12551
Abstract: Multiple loss-of-function mutations in TRIAD3 (a.k.a. RNF216) have recently been identified in patients suffering from Gordon Holmes syndrome (GHS), characterized by cognitive decline, dementia, and movement disorders. TRIAD3A is an E3 ubiquitin ligase that recognizes and facilitates the ubiquitination of its target for degradation by the ubiquitin-proteasome system (UPS). Here, we demonstrate that two of these missense substitutions in TRIAD3 (R660C and R694C) could not regulate the degradation of their neuronal target, activity-regulated cytoskeletal-associated protein (Arc/Arg 3.1), whose expression is critical for synaptic plasticity and memory. The synaptic deficits due to the loss of endogenous TRIAD3A could not be rescued by TRIAD3A harboring GHS-associated missense mutations. Moreover, we demonstrate that the loss of endogenous TRIAD3A in the mouse hippocampal CA1 region led to deficits in spatial learning and memory. Finally, we show that these missense mutations abolished the interaction of TRIAD3A with Arc, disrupting Arc ubiquitination, and consequently Arc degradation. Our current findings of Arc misregulation by TRIAD3A variants suggest that loss-of-function mutations in TRIAD3A may contribute to dementia observed in patients with GHS driven by dysfunctional UPS components, leading to cognitive impairments through the synaptic protein Arc. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Source Title: Aging Cell
URI: https://scholarbank.nus.edu.sg/handle/10635/173853
ISSN: 14749718
DOI: 10.1111/acel.12551
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