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TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation

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 ubiquitinat...

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Autores principales: Husain, Nilofer, Yuan, Qiang, Yen, Yi‐Chun, Pletnikova, Olga, Sally, Dong Qianying, Worley, Paul, Bichler, Zoë, Shawn Je, H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334534/
https://www.ncbi.nlm.nih.gov/pubmed/27995769
http://dx.doi.org/10.1111/acel.12551
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author Husain, Nilofer
Yuan, Qiang
Yen, Yi‐Chun
Pletnikova, Olga
Sally, Dong Qianying
Worley, Paul
Bichler, Zoë
Shawn Je, H.
author_facet Husain, Nilofer
Yuan, Qiang
Yen, Yi‐Chun
Pletnikova, Olga
Sally, Dong Qianying
Worley, Paul
Bichler, Zoë
Shawn Je, H.
author_sort Husain, Nilofer
collection PubMed
description 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.
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spelling pubmed-53345342017-04-01 TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation Husain, Nilofer Yuan, Qiang Yen, Yi‐Chun Pletnikova, Olga Sally, Dong Qianying Worley, Paul Bichler, Zoë Shawn Je, H. Aging Cell Original Articles 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. John Wiley and Sons Inc. 2016-12-20 2017-04 /pmc/articles/PMC5334534/ /pubmed/27995769 http://dx.doi.org/10.1111/acel.12551 Text en © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Husain, Nilofer
Yuan, Qiang
Yen, Yi‐Chun
Pletnikova, Olga
Sally, Dong Qianying
Worley, Paul
Bichler, Zoë
Shawn Je, H.
TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
title TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
title_full TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
title_fullStr TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
title_full_unstemmed TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
title_short TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
title_sort triad3/rnf216 mutations associated with gordon holmes syndrome lead to synaptic and cognitive impairments via arc misregulation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334534/
https://www.ncbi.nlm.nih.gov/pubmed/27995769
http://dx.doi.org/10.1111/acel.12551
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