The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization

Autism spectrum disorders (ASDs) are clinically characterized by decreased communication abilities, impaired social interaction, and the occurrence of repetitive behaviors, with high genetic heritability. Ubiquitin protein ligase E3A (UBE3A) is a gene located on human chromosome 15q11-13, a region t...

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Main Author: Khatri, Natasha
Language:en_US
Published: 2017
Subjects:
Online Access:https://hdl.handle.net/2144/23414
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spelling ndltd-bu.edu-oai-open.bu.edu-2144-234142019-01-08T15:42:16Z The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization Khatri, Natasha Neurosciences Autism spectrum disorders (ASDs) are clinically characterized by decreased communication abilities, impaired social interaction, and the occurrence of repetitive behaviors, with high genetic heritability. Ubiquitin protein ligase E3A (UBE3A) is a gene located on human chromosome 15q11-13, a region that has been the focus of genetic studies of susceptibility to ASD AND Angelman syndrome. An increased UBE3A gene dosage and thus an elevated amount of E6AP, the protein product of UBE3A, is associated with ASD. However, the underlying cellular and molecular details remain poorly understood. Normal development of neuronal structure is critical for intercellular connectivity and overall brain function, and abnormal brain development is a commonality amongst ASDs. These studies therefore investigated the role of increased dosage of Ube3A/E6AP in dendritic arborization and synapse maturation during brain development. Increased E6AP expression in vitro led to significant reduction in dendritic arborization by thinning and fragmentation of the distal tip, along with a decrease in spine density and an increase in immature spines in hippocampal neurons. This morphological remodeling effect was mediated by the ubiquitination and subsequent degradation of the X-linked inhibitor of apoptosis protein (XIAP) by E6AP, which led to activation of caspase-3. Furthermore, activated caspases cleaved tubulin, leading to retraction of microtubules from the distal tip of dendrites, dendritic thinning and eventual disappearance. In vivo studies investigated the role of E6AP in ASD-related neuronal development in Ube3A 2X transgenic mice and found that, consistent with our in vitro studies, increased E6AP in the brain lead to decreased XIAP levels, increased active caspase-3, and enhanced tubulin cleavage in hippocampal tissue in Ube3A 2X mice. In accord, Ube3A 2X mice showed a reduction in dendritic growth and branching and spine density. This work elucidated an important role of Ube3A/E6AP in dendritic pruning and identified XIAP as a novel ubiquitination target of E6AP. These findings provide a new insight into the molecular pathways underlying neurodevelopmental defects in Ube3A/E6AP-associated ASDs. 2018-07-09T00:00:00Z 2017-08-17T14:23:47Z 2017 2017-07-10T01:14:20Z Thesis/Dissertation https://hdl.handle.net/2144/23414 en_US
collection NDLTD
language en_US
sources NDLTD
topic Neurosciences
spellingShingle Neurosciences
Khatri, Natasha
The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization
description Autism spectrum disorders (ASDs) are clinically characterized by decreased communication abilities, impaired social interaction, and the occurrence of repetitive behaviors, with high genetic heritability. Ubiquitin protein ligase E3A (UBE3A) is a gene located on human chromosome 15q11-13, a region that has been the focus of genetic studies of susceptibility to ASD AND Angelman syndrome. An increased UBE3A gene dosage and thus an elevated amount of E6AP, the protein product of UBE3A, is associated with ASD. However, the underlying cellular and molecular details remain poorly understood. Normal development of neuronal structure is critical for intercellular connectivity and overall brain function, and abnormal brain development is a commonality amongst ASDs. These studies therefore investigated the role of increased dosage of Ube3A/E6AP in dendritic arborization and synapse maturation during brain development. Increased E6AP expression in vitro led to significant reduction in dendritic arborization by thinning and fragmentation of the distal tip, along with a decrease in spine density and an increase in immature spines in hippocampal neurons. This morphological remodeling effect was mediated by the ubiquitination and subsequent degradation of the X-linked inhibitor of apoptosis protein (XIAP) by E6AP, which led to activation of caspase-3. Furthermore, activated caspases cleaved tubulin, leading to retraction of microtubules from the distal tip of dendrites, dendritic thinning and eventual disappearance. In vivo studies investigated the role of E6AP in ASD-related neuronal development in Ube3A 2X transgenic mice and found that, consistent with our in vitro studies, increased E6AP in the brain lead to decreased XIAP levels, increased active caspase-3, and enhanced tubulin cleavage in hippocampal tissue in Ube3A 2X mice. In accord, Ube3A 2X mice showed a reduction in dendritic growth and branching and spine density. This work elucidated an important role of Ube3A/E6AP in dendritic pruning and identified XIAP as a novel ubiquitination target of E6AP. These findings provide a new insight into the molecular pathways underlying neurodevelopmental defects in Ube3A/E6AP-associated ASDs. === 2018-07-09T00:00:00Z
author Khatri, Natasha
author_facet Khatri, Natasha
author_sort Khatri, Natasha
title The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization
title_short The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization
title_full The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization
title_fullStr The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization
title_full_unstemmed The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization
title_sort autism protein ube3a/e6ap regulates remodeling of neuronal dendritic arborization
publishDate 2017
url https://hdl.handle.net/2144/23414
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