Abstract
UBE3A is a gene implicated in neurodevelopmental disorders. The protein product of UBE3A is the E3 ligase E6-associated protein (E6AP), and its expression in the brain is uniquely regulated via genetic imprinting. Loss of E6AP expression leads to the development of Angelman syndrome (AS), clinically characterized by lack of speech, abnormal motor development, and the presence of seizures. Conversely, copy number variations (CNVs) that result in the overexpression of E6AP are strongly associated with the development of autism spectrum disorders (ASDs), defined by decreased communication, impaired social interest, and increased repetitive behavior. In this review article, we focus on the neurobiological function of Ube3A/E6AP. As an E3 ligase, many functional target proteins of E6AP have been discovered, including p53, Arc, Ephexin5, and SK2. On a neuronal level, E6AP is widely expressed within the cell, including dendritic arbors, spines, and the nucleus. E6AP regulates neuronal morphological maturation and plays an important role in synaptic plasticity and cortical development. These molecular findings provide insight into our understanding of the molecular events underlying AS and ASDs.
Highlights
The human brain consists of 86 billion neurons, which are connected via trillions of synapses (Azevedo et al, 2009)
Proper gene dosage of UBE3A is crucial to normal brain development, as evidenced by the neurodevelopmental disorders associated with deletions, mutations, and copy number variations (CNVs) of UBE3A
This study provides important information on the cellular function of E6-associated protein (E6AP) in DNA repair and cell cycle progression via regulation of HHR23A levels, the role of this ubiquitination target has not been studied in the context of Angelman syndrome (AS) and autism spectrum disorders (ASDs)
Summary
The human brain consists of 86 billion neurons, which are connected via trillions of synapses (Azevedo et al, 2009). A lack of E6AP led to deficits in the increased activitydependent phosphorylation of the kinase ERK1/2, a process that is important in synaptic plasticity and memory formation (Thomas and Huganir, 2004; Filonova et al, 2014) These studies suggest that E6AP levels are regulated by synaptic activity and that loss of experience and activity-dependent induction of E6AP expression during postnatal development may contribute to ASDs. Proper gene dosage of UBE3A is crucial to normal brain development, as evidenced by the neurodevelopmental disorders associated with deletions, mutations, and copy number variations (CNVs) of UBE3A. Late-onset silencing of paternal Ube3A has been observed in induced pluripotent stem cells (iPSCs) derived from an AS patient (Stanurova et al, 2016) These findings suggest that in AS mice and AS patients, normal development of neurons may occur while paternal E6AP expression remains, but developmental deficits begin to arise as paternal expression diminishes and the lack of maternal expression leads to a complete loss of E6AP function in the brain. This study provides important information on the cellular function of E6AP in DNA repair and cell cycle progression via regulation of HHR23A levels, the role of this ubiquitination target has not been studied in the context of AS and ASD
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