Title: Unraveling the Roles of UBE3A in Neurodevelopment and Neurodegeneration
The role of UBE3A protein in brain development and maturation is well-known, as are the consequences of losing UBE3A expression. Loss of UBE3A protein causes Angelman syndrome (AS), while gain of function is linked to increased risk of developing autism spectrum disorders. UBE3A protein is highly expressed in neurons, but is also found in significant amounts in astrocytes, oligodendrocytes and microglia, types of glial cells.
How UBE3A protein is expressed and functions in glial cells is key to gaining a comprehensive understanding of UBE3A and its role in neurological diseases.
While AS results from a total or near-total loss of UBE3A protein expression, either by mutation or chromosomal deletion, less dramatic decreases in UBE3A protein expression may contribute to the development of common neurodegenerative diseases such as Alzheimer’s Disease (AD). Studies comparing the brains of AD individuals with age-matched healthy brains showed significant decreases in UBE3A protein in multiple brain regions of the AD individuals, with the largest decreases observed in excitatory neurons.
In an AD mouse model, the loss of UBE3A protein exaggerated cognitive deficits, and insoluble UBE3A was found in the same regions as insoluble A-beta peptide (Ab), suggesting UBE3A may somehow interact with Ab peptide. There is also evidence that UBE3A may directly regulate Alzheimer’s Precursor Protein (APP), as AS individuals have increased plasma APP and Ab peptides, and individuals with autism spectrum disorders are predicted to be twice as likely to develop early-onset AD.
Analysis of tissue samples from dup15q individuals showed a decrease in APP relative to neurotypical controls. In addition, UBE3A is one of the most abundant proteins observed in cytosolic pulldown experiments where APP is used as the capture protein, suggesting APP and UBE3A interact in the cytosol. While these data point to a possible role for UBE3A in the regulation of APP and Ab, more studies are required to validate these observations and fully understand the implications for AD.
Other neurodegenerative diseases may also be influenced by changes in UBE3A activity. An AS mouse model showed abnormal dopamine signaling and motor dysfunction, which are common features of Parkinson’s Disease (PD). Huntington’s Disease (HD) mice form Htt protein aggregates in their brains and have decreased levels of UBE3A. Increasing UBE3A in HD mice by using a viral vector led to decreases in aggregation and reduced aggregation-related cell death, suggesting that UBE3A plays a role in the prevention of Htt aggregates. As with the links to AD, these possible roles for UBE3A in HD and PD require additional studies to be sufficiently validated.
In summary, UBE3A expression is critical for brain development and function, and changes in UBE3A levels have significant consequences. A more comprehensive understanding of UBE3A expression in non-neuronal cells is needed, as is an exploration of the potential roles of UBE3A in neurological diseases outside of AS and autism spectrum disorder.
Therapies that target UBE3A activity in any disease will potentially benefit all diseases caused by changes in UBE3A activity or expression.