Defective Enzyme Leads To Autism
August 28, 2013

Impaired Enzymes Linked To Autism, Suggests Environmental Causes Over Genetics

Brett Smith for - Your Universe Online

A team of researchers from the University of North Carolina has found important new information about a group of enzymes that could be used to treat or prevent autism. According to their report in the journal Nature, the scientists found that defecctive or inhibited cellular enzymes called topoisomerases can lead to profound effects during brain development, and potentially to autism spectrum disorder (ASD).

"Our study shows the magnitude of what can happen if topoisomerases are impaired," said study author Mark Zylka, an associate professor in the Neuroscience Center 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."

Zylka emphasized that the findings suggest an environmental rather than genetic cause for autism spectrum disorder (ASD). The findings could also explain why those with genetic mutations that affect topoisomerases develop autism and other similar disorders.

"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.”

Found in all human cells, topoisomerases act to untangle DNA when it becomes wound too tightly, as it frequently does. Some chemotherapy drugs are known to inhibit topoisomerase activity, and Zylka said researchers are racing to uncover other compounds that may have a similar effect.

"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."

The neuroscientist said the team made their discovery by accident while researching topotecan, a topoisomerase-inhibiting chemotherapy drug. While examining the drug’s effects in mouse and human-derived nerve cells, the scientists noticed that topotecan interfered with the proper functioning of extraordinarily long genes. The group then realized that many autism-linked genes are also exceptionally 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."

Fifty of the more than 300 genes that are linked to autism were found to be suppressed by the chemotherapy drug. The research team concluded that this amount of suppression would cause a person who is exposed to a topoisomerase inhibitor during brain development to experience significant neurological effects similar to those seen in an individual who gets ASD as the result of a single defective gene.

The study's findings could also help to bridge the gap between two groups of autism-linked genes. About 20 percent of these genes are related to neuronal synapses and another 20 percent are related to the translating of genetic data into biological functions.

"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."