Mutation Linked to Angelman Syndrome Activates Key Molecular Pathway in Brain Development, Study Finds

Mutation Linked to Angelman Syndrome Activates Key Molecular Pathway in Brain Development, Study Finds

A mutation in the UBE3A gene, whose loss causes Angelman syndrome, activates a molecular pathway that is critical to brain development, new research shows.

The study, “The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome,” appeared in the Journal of Biological Chemistry.

The UBE3A enzyme transfers the small protein ubiquitin to a target protein. Ubiquitin works like a flag, marking the target protein for degradation by a cellular complex called proteasome. This process of inactivating a protein by marking it for degradation with ubiquitin is called ubiquitination.

Interestingly, UBE3A can also flag itself or proteasome molecules for degradation.

A dysfunctioning UBE3A enzyme has been associated with Angelman syndrome, autism, and cancer. While loss of UBE3A causes Angelman syndrome, too much UBE3A increases the risk for autism.

Despite increasing knowledge about the function of UBE3A, scientists still lack information on how its ubiquitination affects brain development.

Abnormal Wnt signaling, which regulates gene transcription (conversion of DNA to RNA) and determines cell fate during development, has been shown in autism and cancer.

The study explored UBE3A function by analyzing its connection with the proteasome and the Wnt signaling pathway. The protein beta-catenin, which is involved in cell development and organ regeneration, is a key element in Wnt signaling.

The Washington University School of Medicine and The University of North Carolina at Chapel Hill research team showed that the autism-linked UBE3AT485A mutation, which enhances UBE3A activity, inhibits the activity of proteasome sub-units.

This also led to a stabilization of beta-catenin, and the activation of one of the Wnt signaling pathways (which leads to the accumulation of beta-catenin and translocation to the cell nucleus), particularly in cells with low basal Wnt activity.

The effect on Wnt activation was greater with the mutated version than with normal UBE3A, the team found. Conversely, the UBE3AT485E mutation, which inhibits UBE3A, did not activate Wnt signaling.

When the team increased the production of diverse proteasome subunits, however, they were able to reverse the effect of the UBE3AT485A mutation on Wnt activity. They also identified which subunits were interacting with UBE3A and Wnt.

Together, this showed that the autism-linked UBE3AT485A mutation exacerbates Wnt signaling by ubiquitinating proteasome subunits and decreasing their activity. As Wnt signaling weakens over the course of development, cells could become more vulnerable to UBE3A excess.

“Our study has broad implications for human disorders associated with UBE3A gain or loss-of-function, and suggests that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity,” the researchers wrote.

The study “provides fundamental new insights into how excess UBE3A could impair brain development and increase risk for autism,” they added.

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