“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.”
“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. ”
Topiosomerases are enzymes prevalent in all human cells and their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.
“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 research team stumbled upon the discovery while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. While 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.
“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.”
There are more than 300 genes that are linked to autism, and 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.
It has long been suspected that there is a genetic connection resulting in ASD symptoms and the findings could provide 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.”
Ian F. King, Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung Huang, Brandon L. Pearson, J. Mauro Calabrese, Joshua Starmer, Joel S. Parker, Terry Magnuson, Stormy J. Chamberlain, Benjamin D. Philpot, Mark J. Zylka. Topoisomerases facilitate transcription of long genes linked to autism. Nature, 2013; DOI: 10.1038/nature12504