Gene with scant role in Parkinson’s research helps flies to walk again
Adding copies of gene, with human counterparts, seen to aid mitochondria
Boosting levels of the Cdk8 gene in fruit flies with Parkinson’s-like symptoms improved their ability to move, possibly due in part to preserving the health of mitochondria, the energy-producing structures within cells, a recent study reports.
While it’s still early to know if this gene’s human counterparts, CDK8 and CDK19, also serve a function that extends beyond their known role in gene regulation, the study suggests they could make up for the loss of PINK1, a gene linked to early-onset Parkinson’s.
“Since many human disease genes have fly counterparts, we can gain valuable knowledge in flies that can be translated to clinical treatments,” Esther Verheyen, PhD, who led the study out of Simon Fraser University (SFU) in British Columbia, Canada, said in a university news story.
“Anytime you learn something more about how a disease occurs or how that disease might be reversed, it gives you insights into possible drugs that could be used,” said Verheyen, who’s a professor of molecular biology and biochemistry at SFU.
Flies lacking Cdk8 gene previously known for seizures, not movement issues
For Verheyen, her team’s “discovery about Cdk8 was unusual because it hadn’t ever really been considered as being involved with parkinsonism,” a broad term that covers a range of brain diseases with symptoms that, like Parkinson’s, cause slowed movements (bradykinesia), tremor, and rigidity.
Giving the flies extra Cdk8 gene copies “made the mitochondria healthier, it made the flies able to crawl and walk again, and that was really unexpected,” she added.
The study, “Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila,” was published in Nature Communications in collaboration with researchers at Baylor College of Medicine in Texas.
During the course of evolution, the human equivalent of the fruit fly’s Cdk8 gene emerged as a result of a duplication event, giving rise to two distinct genes, CDK8 and CDK19. These genes produce enzymes known as cyclin-dependent kinases, which play a role in regulating gene activity by interacting with an enzyme that participates in the process of transcribing genetic information from DNA.
Earlier work with fruit flies showed that the absence of the Cdk8 gene in neurons, or nerve cells, leads to seizures and shorter lifespans. Researchers now found that reducing this gene’s activity also leads to flies with droopy wings and difficulty climbing to the top of their glass vials, similar to what happens when flies lack the Pink1 gene — considered a genetic cause of Parkinson’s, particularly in its early-onset form.
Looking closely into the muscles of those fruit flies, they observed that mitochondria had become elongated, compromising their ability to work as intended. Accordingly, the amount of energy in neurons produced by mitochondria was cut by about half.
These changes could be reversed by inserting extra copies of the Cdk8 gene. Similar observations were made when using the human CDK19 gene instead. “We can do genetic tricks to put more of the fly Cdk8 or human CDK19 gene into cells and we were able to make them healthy again,” Verheyen said.
Gene affects the health of mitochondria, a cell’s energy producers
The Cdk8 enzyme — which was present both in the nucleus, where the DNA is stored, and in the cytoplasm, outside of the nucleus — was found to activate Drp1, a protein that’s needed for mitochondrial fission, a splitting mechanism crucial for maintaining healthy mitochondria. (Enzymes are a type of protein that act as catalysts in biochemical reactions.)
The Pink1 protein was found to activate Drp1 at the same site as Cdk8, suggesting they may share a similar function. Having more of Cdk8 in fruit flies with low levels of Pink1 reduced the number of misshapen mitochondria and reduced the levels of reactive oxygen species (ROS), a type of unstable molecule that can damage cellular components.
“We figured out that fly Cdk8 can bypass a defect found in cells that carry a mutation that causes inherited Parkinson’s,” Verheyen said. “This function involves helping cells get rid of defective mitochondria,” a clearance mechanism that’s impaired in parkinsonism.
Having more of the Cdk8 gene — or its human CDK19 counterpart — also helped more fruit flies with low Pink1 protein levels climb further up glass vial walls, suggesting that the Cdk8 gene can rescue locomotor impairments.
“In this study, we show that loss of Cdk8 causes defects that show some similarity” to parkinsonism, the researchers concluded. “These findings suggest [CDK8 and CDK19] may also contribute to aspects of the development of Parkinson’s.”
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