Developing Cutting-Edge Tools to Control and Study Dopamine Signaling
The biological hallmark of Parkinson’s disease (PD) is the progressive loss of dopamine neurons in the brain. In healthy neurons, the neurotransmitter dopamine and its receptors are carefully regulated and transported to facilitate motor function. Many PD-related mutations affect this regulation, but it has been difficult for researchers to fully investigate these complex processes without more sophisticated methods. Chelsie Kadgien, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, has developed and will be testing novel research tools that will allow her to not just study dopamine signaling in greater detail, but to manipulate it and track the effects in real time as well.
Working with her mentors Dr. Matthew J. Kennedy and Dr. Christopher P. Ford at the University of Colorado Anschutz Medical Campus, Dr. Kadgien has created two different methods to control and investigate dopamine signaling in mouse brains. The first method involves reprogramming neurons to produce small proteins called “nanobodies” that bind to dopamine receptors. These nanobodies stick to dopamine receptors right after they are formed inside the cell and prevent them from being shuttled to the cell surface where they are needed, leading to a reduction in dopamine reception — similar to what is caused by certain PD mutations.
Dr. Kadgien can also release the nanobodies from the inside of the cell chemically, allowing her to control when dopamine reception is turned back on and by how much. This will provide insight into how therapies that restore dopamine receptor levels could be used for people with PD.
The second tool that will be tested involves optogenetics, the use of genetically engineered compounds that can be triggered by light. Dr. Kadgien has designed a light-controlled neurotoxin that prevents the release of dopamine from brain cells, mimicking how PD mutations can prevent dopamine signaling. Not only is this neurotoxin activated by light, but it is also reversible. When left in the dark for eight hours, the toxin’s effects wear off and dopamine release is restored. This powerful tool will allow Dr. Kadgien to study dopamine signaling impairments and restoration in a wide range of ways that have never been possible before.
By testing and refining both dopamine pathway manipulation methods, Dr. Kadgien will lead the way for future research into PD therapies that can best restore dopamine signaling and improve the lives of people living with PD. Speaking on what this award means to her, Dr. Kadgien said “I am incredibly honored to be selected for this award amongst many talented peers … [This research] will build the foundation for my career studying how disruptions in communication between brain cells can lead to Parkinson's disease. I hope my work will lead to improvements in quality of life for people living with the disease and their families.”
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