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Tricks to treat Angelman syndrome may lie in ‘clock cells’

by  /  4 July 2016
Like clockwork: Cells that express the paternal copy of the Angelman syndrome gene (top left) also tend to make the circadian clock protein BMAL (bottom left).

This article is more than five years old. Autism research - and science in general - is constantly evolving, so older articles may contain information or theories that have been reevaluated since their original publication date.

A newly discovered phenomenon in cells that regulate the sleep-wake cycle may provide clues for how to treat Angelman syndrome and dup15q syndrome, two autism-related conditions. The report was published 16 June in Scientific Reports1.

Both syndromes involve alterations to UBE3A. Researchers had thought that this gene is expressed from only the copy of chromosome 15 inherited from the mother, and that the paternal copy of UBE3A is silent, via a phenomenon known as imprinting.

The new study shows that some neurons in the brain do express the paternal copy of the gene. These neurons are in the suprachiasmatic nucleus, a ball of cells buried deep in the brain that serves as the time-keeper for the body’s circadian, or sleep-wake, cycle.

In Angelman syndrome, the maternal copy of UBE3A is mutated, leading to developmental delays, epilepsy and problems with speech. Dup15q syndrome, by contrast, stems from a duplication of a segment of the maternal chromosome that includes UBE3A. Children with dup15q may have autism, as well as severe seizures and cognitive problems.

Researchers are working on treating Angelman syndrome by reanimating the paternal copy of UBE3A. Understanding how certain neurons still express the paternal copy of the gene could help researchers develop treatments that have few side effects, says lead researcher Benjamin Philpot, professor of neuroscience at the University of North Carolina at Chapel Hill.

“If we understand more about the mechanism of imprinting, we might get some greater insights into how to specifically regulate it,” he says. The mechanism might also point to a way of silencing the extra maternal copy in dup15q syndrome.

Youthful cells:

The findings underscore the complexity of how the brain controls UBE3A, says Stormy Chamberlain, assistant professor of genetics and genome sciences at the University of Connecticut in Storrs, who was not involved in the work.

“In the past, we painted the story in black and white: Neurons imprinted UBE3A and non-neurons didn’t,” she says. “This study takes the story up a level by showing that only certain types of neurons are imprinted.”

Last year, Philpot and his team reported hints that neurons in the suprachiasmatic nucleus express paternal UBE3A2. The new work confirms this idea.

The neurons that express paternal UBE3A tend to have markers of immaturity. This observation is consistent with the fact that imprinting ramps up after birth, and that immature neurons in newborn mice express paternal UBE3A.

In people, neurons mature later than they do in rodents, so even more neurons may express the paternal copy than in mice, says Chamberlain. “I’m curious how well this finding extends to human brains,” she says.

On the clock:

Many of the subset of neurons in the suprachiasmatic nucleus that express UBE3A are also circadian clock cells. The researchers found that neurons in other brain regions involved in circadian rhythms also express low levels of paternal UBE3A.

Children with Angelman syndrome often have a lot of trouble falling asleep, which is in part regulated by the circadian clock. But the presence of UBE3A in circadian clock cells suggests that these sleep challenges arise elsewhere.

The study hints that there is a relationship between immaturity, the circadian clock and the lack of imprinting, says Janine LaSalle, professor of medical microbiology and immunology at the University of California, Davis, who was not involved in the work.

The next step, Philpot says, is to identify the genes that shut down UBE3A by comparing neurons that have the silenced gene with those that escape imprinting. That finding could allow researchers to devise treatments that involve manipulating the imprinting process.

  1. Jones K.A. et al. Sci. Rep. 6, 28238 (2016) PubMed
  2. Ehlen J.C. et al. J. Neurosci. 35, 13587-13598 (2015) PubMed