Please use this identifier to cite or link to this item: https://doi.org/10.1111/acel.12551
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dc.titleTRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
dc.contributor.authorHusain N.
dc.contributor.authorYuan Q.
dc.contributor.authorYen Y.-C.
dc.contributor.authorPletnikova O.
dc.contributor.authorSally D.Q.
dc.contributor.authorWorley P.
dc.contributor.authorBichler Z.
dc.contributor.authorShawn Je H.
dc.date.accessioned2020-09-01T07:56:51Z
dc.date.available2020-09-01T07:56:51Z
dc.date.issued2017
dc.identifier.citationHusain 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
dc.identifier.issn14749718
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/173853
dc.description.abstractMultiple 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.
dc.publisherBlackwell Publishing Ltd
dc.sourceUnpaywall 20200831
dc.subjectactivity regulated cytoskeleton associated protein
dc.subjectAMPA receptor
dc.subjectprotein
dc.subjectRNF216 protein
dc.subjectTRIAD3 protein
dc.subjectunclassified drug
dc.subjectactivity regulated cytoskeletal-associated protein
dc.subjectAMPA receptor
dc.subjectclathrin
dc.subjectcytoskeleton protein
dc.subjectgonadorelin
dc.subjectnerve protein
dc.subjectprotein binding
dc.subjectRNF216 protein, mouse
dc.subjectubiquitin protein ligase
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectArticle
dc.subjectbrain cell
dc.subjectcarboxy terminal sequence
dc.subjectcognitive defect
dc.subjectcomparative study
dc.subjectcontrolled study
dc.subjectCOS-7 cell line
dc.subjectdegenerative disease
dc.subjectdorsal hippocampus
dc.subjectgene overexpression
dc.subjectgenetic association
dc.subjectgenetic variability
dc.subjectgordon holmes syndrome
dc.subjecthippocampal CA1 region
dc.subjecthippocampal neuronal culture
dc.subjectloss of function mutation
dc.subjectmale
dc.subjectmissense mutation
dc.subjectmolecular weight
dc.subjectmouse
dc.subjectnerve cell plasticity
dc.subjectnonhuman
dc.subjectnonsense mutation
dc.subjectpriority journal
dc.subjectprotein degradation
dc.subjectprotein expression
dc.subjectrat
dc.subjectspatial learning
dc.subjectsynapse
dc.subjectsynaptic transmission
dc.subjectubiquitination
dc.subjectupregulation
dc.subjectanimal
dc.subjectC57BL mouse
dc.subjectcerebellar ataxia
dc.subjectcognitive defect
dc.subjectdeficiency
dc.subjectendocytosis
dc.subjectgene silencing
dc.subjectgenetics
dc.subjectHEK293 cell line
dc.subjecthuman
dc.subjecthypogonadism
dc.subjectmetabolism
dc.subjectmissense mutation
dc.subjectmutation
dc.subjectpathology
dc.subjectspatial memory
dc.subjectSprague Dawley rat
dc.subjectsynaptic transmission
dc.subjectAnimals
dc.subjectCA1 Region, Hippocampal
dc.subjectCerebellar Ataxia
dc.subjectClathrin
dc.subjectCognitive Dysfunction
dc.subjectCytoskeletal Proteins
dc.subjectEndocytosis
dc.subjectGene Knockdown Techniques
dc.subjectGonadotropin-Releasing Hormone
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectHypogonadism
dc.subjectMice, Inbred C57BL
dc.subjectMutation
dc.subjectMutation, Missense
dc.subjectNerve Tissue Proteins
dc.subjectProtein Binding
dc.subjectProteolysis
dc.subjectRats, Sprague-Dawley
dc.subjectReceptors, AMPA
dc.subjectSpatial Memory
dc.subjectSynapses
dc.subjectSynaptic Transmission
dc.subjectUbiquitin-Protein Ligases
dc.subjectUbiquitination
dc.typeArticle
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1111/acel.12551
dc.description.sourcetitleAging Cell
dc.description.volume16
dc.description.issue2
dc.description.page281-292
dc.published.statePublished
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