Target enzyme for epilepsy drugs may also cause sleep loss

A study in fruit flies shows that an enzyme that is a target for epilepsy drugs also contributes for sleeplessness. This has many implications for treating both conditions.

A new study in a mutant fruitfly called sleepless (sss) confirmed that the enzyme GABA transaminase, which is the target of some epilepsy drugs, contributes to sleep loss. The findings, published online in Molecular Psychiatry, were led by Amita Sehgal, PhD, head of the Chronobiology Program at the University of Pennsylvania's Perelman School of Medicine. The findings shed light on mechanisms that may be shared between sleep disruption and some neurological disorders. A better understanding of this connection could enable treatments that target both types of symptoms and perhaps provide better therapeutic efficacy.

"Epilepsy is essentially an increase-in-firing disorder of the brain and maybe a decrease in activity of the neurotransmitter GABA, too," says Sehgal, who is also a professor of Neuroscience and an investigator with the Howard Hughes Medical Institute (HHMI). "This connects our work to drugs that inhibit GABA transaminase. Changes in GABA transaminase activity are implicated in epilepsy and some other psychiatric disorders, which may account for some of the associated sleep problems."

The team looked at the proteomics of the sss mutant brain -- a large-scale study of the structure and function of related proteins -- and found that GABA transaminase is increased in the sss brain compared to controls. This enzyme breaks down GABA, so GABA is decreased in the sss brain. Because GABA promotes sleep, there is a decrease in sleep in the sss mutant fly, as the name implies.

The relationship between the SSS protein and GABA is not fully understood. The SSS protein controls neural activity, and its absence results in increased neural firing, which likely uses up a lot of energy, says Sehgal. GABA transaminase works in the mitochondria, the energy-production organelle in the glial cells of the brain, which provide fuel for neurons. The large energy demand created by the increased neural firing in sss brains probably alters mitochondrial metabolism, including GABA transaminase function in glia.

In the sss mutant fly, there is a stream of connections that leads to its signature loss of sleep: The sss mutant has increased neuron firing caused by downregulation of a potassium channel protein called Shaker. Recently, the Sehgal lab showed that SSS also affects activity of acetylcholine receptors. Both of these actions may directly cause an inability to sleep. In addition, increased energy demands on glia, which increase GABA transaminase and decrease GABA, may further contribute to sleep loss. On the other hand, if GABA is increased, then sleep is increased, as in flies that lack GABA transaminase.

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Enzymes may be why autism develops

A study from the NIH shows that a group of enzymes may be the cause that autism develops.

A group of enzymes in the brain appears to be key to the activity of many genes linked to autism, a new study reveals.

Experts hope the findings will shed light on the causes of autism, and possibly lead to new treatments.

The study results, published online Aug. 28 in the journal Nature, hint that if disruptions in enzymes called topoisomerases occur during brain development, they might contribute to the development of autism spectrum disorders.

The enzymes are found throughout the body, and their main job is to "untangle the knots" in cells' DNA so the cells can function and reproduce themselves normally, explained senior researcher Mark Zylka, an associate professor of cell biology at the University of North Carolina at Chapel Hill.

Topoisomerases have been well studied for their role in helping tumor cells to spread, and drugs that inhibit the enzymes are already used to treat certain cancers.

There have also been hints, though, that topoisomerases might contribute to autism. Last year, researchers reported that some people with autism spectrum disorders have mutations in these enzymes.

"But we've known little about how they work in the brain," said Zylka.

In lab experiments with mouse and human brain cells, Zylka's team found that a topoisomerase-inhibiting drug reduced the activity of 49 genes that past studies have linked to autism. That points to the importance of topoisomerases in the normal expression of those genes.

"A single drug down-regulated all of those genes," Zylka said.

That does not mean, however, that topoisomerase inhibitors should be tested for treating autism. If anything, Zylka explained, you would want a drug that enhances the enzymes' actions.

But now researchers can look for compounds that do just that.

What's more, the findings point to a biological process that ties together dozens of different genes that are suspected of being involved in autism. "Well over 300 (autism-linked) genes have been identified now," Zylka said. "That list looks daunting, but the goal is to figure out how all these genes are connected," he said.

"It can be overwhelming when you look at the list of genes," agreed Andy Shih, senior vice president for scientific affairs for the advocacy group Autism Speaks.

But if you can zero in on the "biological pathways" linking those genes, "it all starts to make sense," said Shih, who was not involved in the study.

In the United States, it's estimated that at least one in every 88 children has an autism spectrum disorder, with the severity ranging widely from child to child. Some kids have little or no ability to speak, and focus obsessively on just a few interests; other kids speak and have normal to above-normal intelligence, but may have problems socializing and communicating more subtly -- for example, trouble using and "reading" gestures, body language and facial expressions.

No one knows what causes autism spectrum disorders, but experts believe that it's a complex mix of genetic vulnerability and environmental exposures -- possibly chemicals or microbes.

Shih pointed to an "interesting" fact about topoisomerases: Their activity is believed to be influenced by environment, including compounds in food and in the physical world. So, he said, studying the enzymes might help researchers pinpoint some of the environmental factors that contribute to autism spectrum disorders.

"We've been talking for a long time about the interaction between genes and environment in autism," Shih said. Topoisomerases could offer a way for scientists to begin to connect the dots.

Zylka agreed, and said his team is searching for environmental compounds that inhibit topoisomerases -- and may, therefore, be important for pregnant women or young children to avoid.

There is still, however, a long way to go in fully understanding the underpinnings of autism spectrum disorders. "We've just scratched the surface of what's going wrong in the brain" in autism, Zylka said.

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Problems with enzymes linked to genes associated with autism

Research shows that issues with a type of enzyme is linked to a group of genes associated with autism development.

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research announced today in the journal Nature. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder's genetic causes.

"Our study shows the magnitude of what can happen if topoisomerases are impaired," said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. "Inhibiting these enzymes has the potential to profoundly affect neurodevelopment -- perhaps even more so than having a mutation in any one of the genes that have been linked to autism."

The study could have important implications for ASD detection and prevention.

"This could point to an environmental component to autism," said Zylka. "A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. "

This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. "If there are additional compounds like this in the environment, then it becomes important to identify them," said Zylka. "That's really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects -- so that pregnant women can avoid being exposed to these compounds."

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug's effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long -- composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.

"That's when we had the 'Eureka moment,'" said Zylka. "We realized that a lot of the genes that were suppressed were incredibly long autism genes."

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board -- even to a small extent -- means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study's findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses -- the connections between brain cells. Another 20 percent are related to gene transcription -- the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person's ability to construct synapses.

"Our discovery has the potential to unite these two classes of genes -- synaptic genes and transcriptional regulators," said Zylka. "It could ultimately explain the biological mechanisms behind a large number of autism cases."

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