Breakthrough study offers hope for slowing down Parkinson’s disease

Over 8.5 million individuals were living with Parkinson's Disease (PD) in 2019 globally. The prevalence has doubled in the past 25 years, according to the WHO. What makes this neurodegenerative disorder especially concerning is that it results in high rates of disability. A recent discovery about the consequences of neuron overactivity could lead to new methods of treating or preventing Parkinson’s disease.

A new study led by the scientists at Gladstone Institutes found that overworked brain cells may burn out in Parkinson’s disease. The findings of the study were published in the scientific journal eLife.

Parkinson’s disease and neuron overactivity

A progressive neurodegenerative disorder, PD affects the brain's ability to produce dopamine, causing problems with movement, mental health, sleep, pain, and other cognitive difficulties. It is a progressive condition, meaning the symptoms get worse over time. It usually occurs in older adults; however, it can also affect young people.

There are certain brain cells responsible for coordinating smooth, controlled movements of the body. However, when these cells are constantly overactivated for weeks on end, they degenerate and ultimately die. This new observation may help explain what goes awry in the brains of people with Parkinson’s disease.

Though previous research has found that a particular subset of neurons dies as Parkinson’s disease progresses, they weren’t sure why it happens. The new research sheds light on this. The study in mice shows that chronic activation of these neurons can directly cause their death. The researchers came to a hypothesis that in Parkinson’s, neuron overactivation could be triggered by a combination of genetic factors, environmental toxins, and the need to compensate for other neurons that are lost.

“An overarching question in the Parkinson’s research field has been why the cells that are most vulnerable to the disease die. Answering that question could help us understand why the disease occurs and point toward new ways to treat it,” Gladstone Investigator Ken Nakamura, MD, PhD, who led the study, said in a statement.

Too much buzz

The global prevalence of Parkinson’s Disease is surging. This condition causes tremors, slowed movement, stiff muscles, and problems walking and balancing. The scientists know that certain neurons that produce dopamine and support voluntary movement die in those with these conditions. There are also evidence on how the activity of these cells actually increases with disease, both before and after degeneration begins. However, whether this change in activity can directly cause cell death was unknown.

The new study tackles this question. The researchers introduced a receptor into dopamine neurons in mice. This receptor allowed them to increase the cells’ activity by treating the animals with a drug, clozapin-N-oxide (CNO). They added CNO to the animals’ drinking water, driving chronic activation of the neurons.

“In previous work, we and others have transiently activated these cells with injections of CNO or by other means, but that only led to short bursts of activation. By delivering CNO through drinking water, we get a relatively continuous activation of the cells, and we think that’s important in modeling what happens in people with Parkinson’s disease,” Katerina Rademacher, a graduate student in Nakamura’s lab and first author of the study, said.

The mice's typical cycle of daytime and nighttime activities was disrupted within a few days of overactivating the dopamine neurons. They detected degeneration of the long projections (called axons) extending from some dopamine neurons in a week. The neurons started to die in a month.


Most importantly, these changes primarily affected one subset of dopamine neurons in the substantia nigra, a brain region that controls movement, while sparing dopamine neurons in areas tied to motivation and emotions. This is the same pattern of cellular degeneration seen in people with Parkinson’s disease.

A link to human disease

To understand why overactivation leads to neuronal degeneration, the researchers studied the molecular changes that occurred in the dopamine neurons before and after the overactivation. They noticed that the overactivation of the neurons results in changes in calcium levels and in the expression of genes linked to dopamine metabolism.

“In response to chronic activation, we think the neurons may try to avoid excessive dopamine—which can be toxic—by decreasing the amount of dopamine they produce. Over time, the neurons die, eventually leading to insufficient dopamine levels in the brain areas that support movement,” Rademacher said.

They measured the changes in brain samples collected from patients with early-stage Parkinson’s, and found similar changes. The genes linked to dopamine metabolism, calcium regulation, and healthy stress responses were turned down.

“This study raises the exciting possibility that adjusting the activity patterns of vulnerable neurons with drugs or deep brain stimulation could help protect them and slow disease progression,” Nakamura concluded.