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Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease

Synaptic dysfunction and synapse loss are prominent features in Alzheimer’s disease. Members of the Rho-family of guanosine triphosphatases, specifically RhoA, and the synaptic protein Arc are implicated in these pathogenic processes. They share a common regulatory molecule, the E3 ligase Ube3A/E6-A...

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Autores principales: Olabarria, Markel, Pasini, Silvia, Corona, Carlo, Robador, Pablo, Song, Cheng, Patel, Hardik, Lefort, Roger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430817/
https://www.ncbi.nlm.nih.gov/pubmed/30937395
http://dx.doi.org/10.1038/s42003-019-0350-5
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author Olabarria, Markel
Pasini, Silvia
Corona, Carlo
Robador, Pablo
Song, Cheng
Patel, Hardik
Lefort, Roger
author_facet Olabarria, Markel
Pasini, Silvia
Corona, Carlo
Robador, Pablo
Song, Cheng
Patel, Hardik
Lefort, Roger
author_sort Olabarria, Markel
collection PubMed
description Synaptic dysfunction and synapse loss are prominent features in Alzheimer’s disease. Members of the Rho-family of guanosine triphosphatases, specifically RhoA, and the synaptic protein Arc are implicated in these pathogenic processes. They share a common regulatory molecule, the E3 ligase Ube3A/E6-AP. Here, we show that Ube3A is reduced in an Alzheimer’s disease mouse model, Tg2576 mouse, which overexpresses human APP695 carrying the Swedish mutation, and accumulates Aβ in the brain. Depletion of Ube3A precedes the age-dependent behavioral deficits and loss of dendritic spines in these mice, and results from a decrease in solubility following phosphorylation by c-Abl, after Aβ exposure. Loss of Ube3A triggers the accumulation of Arc and Ephexin-5, driving internalization of GluR1, and activation of RhoA, respectively, culminating in pruning of synapses, which is blocked by restoring Ube3A. Taken together, our results place Ube3A as a critical player in Alzheimer’s disease pathogenesis, and as a potential therapeutic target.
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spelling pubmed-64308172019-04-01 Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease Olabarria, Markel Pasini, Silvia Corona, Carlo Robador, Pablo Song, Cheng Patel, Hardik Lefort, Roger Commun Biol Article Synaptic dysfunction and synapse loss are prominent features in Alzheimer’s disease. Members of the Rho-family of guanosine triphosphatases, specifically RhoA, and the synaptic protein Arc are implicated in these pathogenic processes. They share a common regulatory molecule, the E3 ligase Ube3A/E6-AP. Here, we show that Ube3A is reduced in an Alzheimer’s disease mouse model, Tg2576 mouse, which overexpresses human APP695 carrying the Swedish mutation, and accumulates Aβ in the brain. Depletion of Ube3A precedes the age-dependent behavioral deficits and loss of dendritic spines in these mice, and results from a decrease in solubility following phosphorylation by c-Abl, after Aβ exposure. Loss of Ube3A triggers the accumulation of Arc and Ephexin-5, driving internalization of GluR1, and activation of RhoA, respectively, culminating in pruning of synapses, which is blocked by restoring Ube3A. Taken together, our results place Ube3A as a critical player in Alzheimer’s disease pathogenesis, and as a potential therapeutic target. Nature Publishing Group UK 2019-03-22 /pmc/articles/PMC6430817/ /pubmed/30937395 http://dx.doi.org/10.1038/s42003-019-0350-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Olabarria, Markel
Pasini, Silvia
Corona, Carlo
Robador, Pablo
Song, Cheng
Patel, Hardik
Lefort, Roger
Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease
title Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease
title_full Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease
title_fullStr Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease
title_full_unstemmed Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease
title_short Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease
title_sort dysfunction of the ubiquitin ligase e3a ube3a/e6-ap contributes to synaptic pathology in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430817/
https://www.ncbi.nlm.nih.gov/pubmed/30937395
http://dx.doi.org/10.1038/s42003-019-0350-5
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