Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

Abstract

Summary The E3 ubiquitin ligase protein UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse, and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies.

Glial overexpression of Dube3a causes seizures and synaptic impairments in Drosophila concomitant with down regulation of the Na+/K+ pump ATPα

“…AS is caused by reciprocal deletions of the maternal 15q11.2-q13.1 region, methylation defects, or loss-of-function point mutations which result in non-functional UBE3A (LaSalle et al, 2015). Due to the well-established link between UBE3A loss and seizures in AS, we predict that UBE3A may similarly underlie seizures in Dup15q.…”

The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

“…UBE3A is an E3 ubiquitin ligase that targets several substrate proteins, including itself, for proteasomal degradation (9). While much has been learned from studying postnatal functions for UBE3A in mature neurons (10)(11)(12)(13), precisely how ubiquitination of these proteins, or other yet to be identified substrates, affects brain development is largely unclear. Here, we sought to gain new insights into developmental functions for UBE3A by exploring a novel connection between UBE3A, the proteasome, and the Wnt signaling pathway.…”

Perturbed proteostasis in autism spectrum disorders

“…One notable exception to this is Angelman syndrome (AS), a neurodevelopmental disorder caused by disruption of the E3 ligase Ube3a, which is characterized by ID, developmental delay, seizures, motor disruptions, and an unusually positive demeanor (LaSalle et al 2015). While the majority of cases are caused by the specific loss of the maternal UBE3A allele, several studies have shown that mutations affecting the catalytic domain of Ube3a can also result in AS symptomology (Kishino et al 1997;Matsuura et al 1997;Cooper et al 2004).…”

“…Missense mutations targeting an inhibitory phosphorylation site on Ube3a have also been identified as risk factors for developing ASD/ID (Yi et al 2015). Interestingly, the duplication or triplication of the chromosomal region 15q11-q13 in which the UBE3A gene resides is a major cytogeneic risk factor for ASD (LaSalle et al 2015). While it is not clear that this is due directly to the increased level of Ube3a, transgenic mice engineered to express multiple copies of the Ube3a gene exhibit impaired social behavior and communication, and increased repetitive behaviors (Smith et al 2011).…”

“…Given the many neurological phenotypes associated with changes in Ube3a expression, one major task in the field has been to identify brain-derived targets as disease-relevant substrates (LaSalle et al 2015). The most studied Ube3a substrate is Arc/Arg3.1, a cytoskeleton-associated protein known to regulate trafficking of AMPARs to the membrane (Greer et al 2010).…”