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Key enzymes are found to have a ‘profound effect’ across dozens of genes linked to autism. The insight could help illuminate environmental factors behind autism spectrum disorder and contribute to a unified theory of how the disorder develops.
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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.
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Topoisomerase inhibitors reduce the expression of long genes in neurons, including a remarkable number of genes implicated in Autism Spectrum Disorders.
Our
study shows the magnitude of what can happen if topoisomerases are
impaired. Inhibiting these enzymes has the potential to profoundly
affect neurodevelopment ...
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“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.”
The study’s coauthors include Benjamin Philpot (co-senior author),
Terry Magnuson, Ian King, Chandri Yandava, Angela Mabb, Hsien-Sung
Huang, Brandon Pearson, J. Mauro Calabrese, Joshua Starmer and Joel
Parker from UNC and Jack S. Hsiao and Stormy Chamberlain of the
University of Connecticut Health Center.
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