A study published in eLife seeks to explain why Dopamine neurons die in Parkinson’s patients. Dopamine is a neurotransmitter in the brain with many essential roles. It’s our feel-good chemical when we experience euphoria from running a marathon, earning an A on a tough paper you stayed up late to finish for class, or winning an award. It also helps you walk upright and coordinate muscle movements. Additionally, dopamine regulates hormone release and affects blood flow, heart rate, and kidney function. We all rely on these functions to get through our day smoothly, but for Parkinson’s patients, the loss of dopamine can lead to debilitating day-to-day effects, both mentally and physically.
Researchers are trying to understand why these dopamine neurons are dying off in patients with Parkinson’s. Several studies have indicated that the firing of the surviving dopamine neurons actually increases in Parkinson’s patients during the disease’s early stages and while the disease is progressing, becoming overactive while other neurons around them die off. Researchers are left wondering if this is the brain’s way of responding to the cell loss taking place, or if this is a direct cause of the degenerative loss of dopamine?
To test the theory, researchers led by Ken Nakamura, M.D. Ph.D. at Gladstone Institutes developed a model for mice using a “chemogenetic” tool. In short, it is a brain receptor or a special switch that scientists added only to the dopamine-making cells in the mice, which can be activated using an inert drug called clozapine-N-oxide in their drinking water, ensuring that the special receptor is active and mimicking a state of chronic hyperactivity.
There were several changes just after a few days that resembled the symptoms of Parkinson’s Disease, including disturbed sleeping patterns, suggesting that their circadian rhythm and behavior had changed due to the excessive amounts of dopamine, which also mimics the irregular sleep patterns seen in Parkinson’s patients, showing that when dopamine activity is disrupted, your body’s natural rhythm is thrown off (Having trouble sleeping?) and cause irregular or reduced movements and your circadian rhythm.
After a month of persistent overactivation, some of the dopamine neuron cell bodies in the midbrain started to die off because of being constantly on, causing neurodegeneration. According to the study results, the loss occurred gradually and was localized to the substantia nigra area of the brain, and signs of cellular distress and calcium overload took place. Researchers believe this was a protective response by the brain because of the excessive activity of firing and releasing dopamine. In response, cells attempted to produce less to prevent toxic buildup when faced with excessive firing and dopamine release to avoid toxic buildup.
The study links direct evidence that overactive dopamine neurons can trigger the same kind of degeneration in Parkinson’s disease, and that, in the case of the mice involved in the study, overactivity can lead to neuron death and not just a byproduct of neuron loss. Researchers state,” The results support a ‘cell burnout’ hypothesis: dopamine neurons that fire too much for too long become exhausted and gradually die, much like an overworked motor that overheats.” This results in other neurons having to work harder to keep dopamine levels up, while the excessive neural activity may be toxic to these areas of the brain.
This study may lead to new areas for therapy aimed at slowing these neurons down through dopamine replacement medications or Deep Brain Stimulation to relieve symptoms. Researchers raise an “exciting possibility” that adjusting the activity patterns of vulnerable neurons might slow the disease using certain types of drugs designed to regulate and slow the progression of the disease. Researchers also suggest that Parkinson’s may be a disease of “overworked neurons,” and efforts to maintain function could have the adverse effect and harm the cells instead. The whole study can be read here at elifesciences.org
Ongoing research reflects the consistent efforts made by researchers and medical professionals to find new treatments, medications, and new surgical breakthroughs, with available treatments described in Living With Parkinson’s: A Changing Landscape of Hope, Tools, and New Discoveries, Part Two, while combating the environmental challenges that have influenced the disease, with more cases spreading worldwide.
Parkinson’s is a disease always on the move and ever changing; new studies lead the way to improving the quality of life for the millions of patients around the world.
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