A Houston Methodist researcher has unveiled a novel function of the cyclin-dependent kinase protein CDK19, a potential target for the prevention and treatment of Parkinson's and other disorders of the nervous system.
In a new study highlighting CDK19's surprising role in mitochondrial dynamics, Hyunglok Chung, Ph.D., and colleagues found the gene located in the cytoplasm of brain and muscle cells, suggesting it plays a key part in neurologic health.
"Mitochondrial dysfunction is a hallmark of several human diseases, so finding a new gene that influences it is very exciting," said Dr. Chung, an assistant professor of genetics in the Department of Neurology at the Houston Methodist Research Institute and a first author on the paper. "This is very much a hot topic in neurodegenerative disease research because we're learning more and more how disruptions to the normal processing of cellular energy production in mitochondria can lead to the development of disease."
The research was published in April in Nature Communications.
Traditionally known for its involvement in transcription regulation, recent research has uncovered a novel role for CDK19 in the regulation of mitochondrial fission. This process is crucial for maintaining cellular health, as it ensures the proper distribution and function of mitochondria within cells.
Mitochondrial fission is particularly significant in neurons due to their high energy demands and complex architecture. Dysregulation of this process has been implicated in various neurodegenerative diseases, including Parkinson's disease. The research team identified a significant connection between the cyclin-dependent kinase protein and Pink1, a well-established Parkinson's disease-causing gene.
Overexpression of CDK19 in Pink1 mutant fruit flies significantly mitigated Parkinsonian phenotypes, suggesting a compensatory mechanism.
"By demonstrating that CDK19 functions downstream of Pink1, helps regulate mitochondrial fission, and can compensate for the deficiency of Pink1, our study reveals an important potential therapeutic avenue for the prevention or management of Parkinson's disease," Dr. Chung explained.
In detail, the study shows that CDK19 can alleviate the mitochondrial dysfunction typically observed in Pink1-deficient models. This was evidenced by improved mitochondrial morphology and function in CDK19-overexpressing Pink1 mutant flies.
This discovery provides a promising strategy for targeting mitochondrial dynamics in Parkinson's disease and underscores the therapeutic potential of modulating the gene's activity in neurodegenerative disorders.
Ironically, the discovery of the gene's unexpected cytoplasmic function wasn't sparked by an interest in Parkinson's or any other major disease, but rather a follow-up to previous research looking into an ultra-rare disorder caused by CDK19 variants.
"We identified three patients with this variant who displayed classic neurological symptoms like intellectual disability, infantile seizures, and hypermyelination," Dr. Chung said. "I was curious why a mutation in this supposedly nucleus-bound protein would cause so much neurological damage, so I started looking at where it was expressed in the brain."
Meanwhile, a research team from Simon Fraser University in Canada, led by Dr. Esther Verheyen, found the gene in a similarly unexpected non-nuclear location within the mitochondria of muscle tissue.
Dr. Chung and Dr. Verheyen teamed up to investigate the mechanisms of the cyclin-dependent kinase protein and its fruit fly orthologue Cdk8.
In Drosophila models, both muscle-specific and neuron-specific knockdowns of Cdk8 resulted in decreased levels of pS616-Drp1, a dynamin-related protein essential for mitochondrial fission. Conversely, overexpression of Cdk8 increased pS616-Drp1 levels, confirming its role in promoting mitochondrial health.
The study underscores the importance of interdisciplinary approaches in scientific discovery.
Dr. Chung emphasizes the collaborative nature of the research, bridging expertise from different labs to unravel the complexities of mitochondrial dynamics. "Our collaboration with Dr. Verheyen's lab was pivotal in uncovering this gene's role in mitochondrial dynamics and its connection to Parkinson's disease," he said.
Future studies will aim to validate the researchers' findings in human cell models and explore therapeutic interventions targeting CDK19 mutations.
Investigations will continue in both the rare disease phenotype and mitochondrial-related diseases and neurodegenerative disorders associated with the cyclin-dependent kinase protein.
"This is a good example of why no disease should be ignored, no matter how rare," said Dr. Chung. "Not only do those patients and their families deserve answers too, targeted genetic studies often reveal bigger truths about disease and illuminate pathways we didn't know we should be looking at."
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