Researchers Closer to Understanding Role of Enzyme Behind Angelman Syndrome, Study Reports

Researchers from the University of North Carolina have found that ubiquitin protein ligase E3A — the malfunction of which is behind Angelman syndrome development — is present in different types of neurons from the cerebral cortex, where it likely exerts its function.

According to the authors, this could be one of the first steps toward understanding the role ubiquitin plays in Angelman syndrome.

The study, “Subcellular organization of UBE3A in human cerebral cortex,” was published in Molecular Autism.

Angelman syndrome is a genetic neurological disorder caused by the loss or malfunction of the maternal copy of the UBE3A gene. This gene provides instructions for making the enzyme ubiquitin protein ligase E3A that normally targets other proteins to be destroyed at the proteasome — a complex of enzymes responsible for the destruction of unnecessary or damaged proteins.

Conversely, increased ubiquitin activity — through gain-of-function mutations or UBE3A gene duplication — has been linked to several forms of autism, suggesting that ubiquitin activity must be carefully balanced in the body to ensure normal neuronal function.

Despite its clinical relevance for a series of neurological disorders, the exact function of ubiquitin in the human brain and its localization within cells remain unclear.

“Crucial for the elucidation of UBE3A’s [ubiquitin protein ligase E3A] functions is to determine where the protein actually lies within the cell. Unique patterns of UBE3A expression within the cerebral cortex could have important functional implications, especially given the cognitive manifestations of both AS [Angelman syndrome] and autism,” the researchers wrote.

“[In this study], we explore this intriguing possibility by investigating the subcellular [within cells] distribution of UBE3A in the human temporal cortex,” they added.

The cerebral cortex is the brain area responsible for higher thought processes including speech and decision-making. It is divided into four different lobes, or areas, including the temporal cortex, which mainly revolves around hearing and selective listening. This area receives sensory information, such as sounds and speech from the ears, and is key to being able to comprehend or understand meaningful speech.

To find where ubiquitin was located within neurons from the human cerebral cortex, researchers used a technique called light and electron microscopic immunohistochemistry in nine brain sample biopsies obtained from patients undergoing surgery to remove epileptic foci (regions) from the hippocampus — a region of the brain involved in long-term memory formation.

Ubiquitin was present in both excitatory, or glutamatergic, neurons, those that promote neuronal activity, and inhibitory neurons, or GABAergic, those that prevent neuronal activity, and to a lesser extent, in glial cells, which are the cells that support neurons.

Excitatory and inhibitory neural signals are the “yin and yang” of the brain. Excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire. This is the basis of communication between nerve cells in the brain.

In addition, researchers found that the distribution of ubiquitin within neurons was not uniform. Ubiquitin accumulated in specific regions of the cell nucleus but was also present in dendrites and axons — the long, slender projections of a nerve cell that carry an electrical signal from the cell body to the point of contact with another nerve cell, known as the synapse.

“That UBE3A is expressed at high levels in both excitatory and inhibitory neurons in the human cerebral cortex points to the many ways that its dysregulation might disrupt circuit function, while its concentration at synapses [junctions between two nerve cells that allow them to communicate] and in nuclei offers intriguing functional clues,” the researchers wrote.

“UBE3A in axon terminals presumably regulates the function of individual synapses; in contrast, its concentration in nuclear domains [containing genes that are highly expressed] suggests that UBE3A may also mediate global effects on neuronal physiology, by regulating gene transcription,” they said.

Of note, gene transcription refers to the process by which DNA is converted into RNA, before being converted into a protein.

According to the team, axon terminals and nuclei are two distinct potential targets for future clinical intervention.