Screen Readers Skip to Content
🖶 Print page

Top2A Gene Could be Key to Understanding Autism

Published: 2022-11-26
Author: University of Utah Health | Contact: utah.edu
Peer-Reviewed Publication: Yes
Library of Related Papers: Autism Information Publications

Synopsis: This study helps us understand at the molecular level why sociability is disrupted during the very earliest stages of life. Little is known about how social behavior develops in the earliest stages of life. But most animals - including humans - are born with an innate ability to interact socially or form bonds with others. And that contributes to success throughout life. Findings suggest that the gene - TOP2a - controls an extensive network of genes that are known to increase the risk of autism. It also may serve as a link between genetic and environmental factors that contribute to the onset of the disorder

advertisements

Definition

TOP2a

DNA topoisomerase IIα is a human enzyme encoded by the TOP2A gene. Topoisomerase IIα relives topological DNA stress during transcription, condenses chromosomes, and separates chromatids. It catalyzes the transient breaking and rejoining of two duplex DNA strands, allowing them to pass through one another. Two forms of this enzyme are likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17, and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents, and various mutations in this gene have been associated with developing drug resistance.

Main Digest

Little is known about how social behavior develops in the earliest stages of life. But most animals - including humans - are born with an innate ability to interact socially or form bonds with others. And that contributes to success throughout life.

Related Publications:

A new animal study points to a gene important for the earliest development of basic social behaviors.

The work also suggests that exposure to certain drugs and environmental risk factors during embryonic development can cause changes to this gene, leading to alterations in social behavior that are similar to those found in individuals who have autism. To their surprise, the researchers also found they could reverse some effects using an experimental drug.

"This study helps us understand at the molecular level why sociability is disrupted during the very earliest stages of life," says Randall T. Peterson, Ph.D., the corresponding author of the study and dean of the University of Utah College of Pharmacy. "It also allows us to explore potential treatments that could restore sociability in these animals and, perhaps in time, eventually in humans."

More broadly, their findings suggest that the gene - TOP2a - controls a large network of genes that are known to increase the risk of autism. Peterson adds that it may serve as a link between genetic and environmental factors that they contribute to the onset of the disorder.

The study, conducted by University of Utah Health researchers and colleagues nationwide, appears in the Nov. 23 issue of Science Advances.

(Article continues below image.)
To test if environmental factors could influence social behavior, researchers exposed zebrafish embryos to more than 1,100 known drugs. Normal zebrafish devoted much of their attention on other zebrafish. However, fish exposed to certain drugs experienced a change in the levels of some autism-linked genes, and lost interest in social interaction. These and other experiments suggest that certain environmental exposures may impair development of social behavior by affecting autism-linked genes - Image Credit: Tara Mleynek - University of Utah Health.
To test if environmental factors could influence social behavior, researchers exposed zebrafish embryos to more than 1,100 known drugs. Normal zebrafish devoted much of their attention on other zebrafish. However, fish exposed to certain drugs experienced a change in the levels of some autism-linked genes, and lost interest in social interaction. These and other experiments suggest that certain environmental exposures may impair development of social behavior by affecting autism-linked genes - Image Credit: Tara Mleynek - University of Utah Health.
(Continued...)

Anti-social Animals

Scientists suspect many social traits are determined before birth. But the precise mechanisms involved in this process remain murky. One promising area of research suggests that social behavior and other characteristics and traits are influenced by our genetic makeup and how and where we live.

To test this model, the scientists evaluated whether environmental exposures during embryonic development could influence social behavior. Peterson and his colleagues exposed zebrafish embryos to more than 1,100 known drugs - one drug per 20 embryos - for 72 hours beginning three days after conception.

The researchers determined that four of the 1,120 tested drugs significantly reduced sociability among the zebrafish. Fish exposed to these drugs were less likely to interact with other fish. It turned out that the four medications all belonged to the same class of antibiotics called fluoroquinolones. These drugs treat upper and lower respiratory tract infections in people.

When the scientists gave a related drug to pregnant mice, the offspring behaved differently when they became adults. Even though they appeared normal, they communicated less with other mice and engaged in more repetitive acts-like, repeatedly poking their head in the same hole-than other rodents.

Basis for Sociability

Digging deeper, the researchers found that the drugs suppressed a gene called TOP2a, which, in turn, acted on a cluster of genes that are known to be involved in autism in humans.

They also found that the cluster of autism-associated genes shared another thing in common-a higher than usual tendency to bind a group of proteins called the PRC2. The researchers hypothesized that Top2a and the PRC2 work together to control the production of many autism-associated genes.

To determine whether the anti-social behaviors could be reversed, the research team gave embryonic and young zebrafish an experimental drug called UNC1999, which is known to inhibit the PRC2. After treatment with the drug, fish exposed to fluoroquinolones were likelier to swim closer to other fish, demonstrating that the drug helped restore sociability. They saw similar results with other drugs known to inhibit the same key gene, TOP2a.

"That surprised me because I would've thought disrupting brain development when you're an embryo would be irreversible," Peterson says. "If you don't develop sociality as an embryo, you've missed the window. But this study suggests you can still come in and inhibit this pathway and restore sociality even in those individuals later in life."

The researchers plan to explore how and why this drug had this effect.

Although the scientists only found four compounds that are Top2a inhibitors, evidence suggests hundreds of other drugs and naturally occurring compounds in our environment can inhibit its activity.

"These four compounds may be just the tip of the iceberg in terms of substances that could be problematic for embryonic exposure," Peterson says.

However, Peterson notes that this study was conducted in animals, and more research needs to be done before any of its results can be confirmed in humans. Therefore, he cautions against concluding real-world applications.

"We have no evidence that fluoroquinolones or any other antibiotic causes autism in humans," Peterson says. "So, there is no reason to stop using antibiotics. This paper identifies a new molecular pathway that appears to control social development and is worthy of further exploration."

About the Study

In addition to Dr. Peterson, U of U Health scientists Yijie Geng, Tejia Zhang, Ivy G. Alonzo, Sean C. Godar, Christopher Yates, Brock Plummer, and Marco Bortolato contributed to this study. Other participating institutions include the University of Chicago; Beth Israel Deaconess Medical Center in Boston; Massachusetts General Hospital and Harvard Medical School; the Broad Institute, Cambridge, Massachusetts; and MDI Biological Laboratory, Bar Harbor, Maine.

The study, "Top2a promotes the development of social behavior via PRC2 and H3K27me3," appeared in the Nov. 23, 2022, issue of Science Advances. This research was supported by the L. S. Skaggs Presidential Endowed Chair and the National Institute of Environmental Health Sciences at the National Institutes of Health.

Attribution/Source(s):

This peer reviewed article relating to our autism information section was selected for publishing by the editors of Disabled World due to its likely interest to our disability community readers. Though the content may have been edited for style, clarity, or length, the article "Top2A Gene Could be Key to Understanding Autism" was originally written by University of Utah Health. Should you require further information or clarification, they can be contacted at utah.edu Disabled World makes no warranties or representations in connection therewith.

Tweet This Add to Facebook Post to Reddit
advertisements

Disabled World is an independent disability community established in 2004 to provide disability news and information to people with disabilities, seniors, their family and/or carers. See our homepage for informative news, reviews, sports, stories and how-tos. You can also connect with us on Twitter and Facebook or learn more on our about us page.

Disabled World provides general information only. The materials presented are never meant to substitute for professional medical care by a qualified practitioner, nor should they be construed as such. Financial support is derived from advertisements or referral programs, where indicated. Any 3rd party offering or advertising does not constitute an endorsement.


Cite This Page (APA): University of Utah Health. (2022, November 26). Top2A Gene Could be Key to Understanding Autism. Disabled World. Retrieved June 2, 2023 from www.disabled-world.com/health/neurology/autism/top2a.php

Permalink: <a href="https://www.disabled-world.com/health/neurology/autism/top2a.php">Top2A Gene Could be Key to Understanding Autism</a>