Chronic neuron overactivation may drive Parkinson's disease progression

Certain brain cells are responsible for coordinating smooth, controlled movements of the body. But when those cells are constantly overactivated for weeks on end, they degenerate and ultimately die. This new observation made by scientists at Gladstone Institutes may help explain what goes awry in the brains of people with Parkinson's disease.

Researchers have long known that a particular subset of neurons die as Parkinson's disease progresses, but they aren't sure why. The new work, published in the scientific journal eLife, shows that in mice, chronic activation of these neurons can directly cause their demise. The scientists hypothesize 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," says Gladstone Investigator Ken Nakamura, MD, PhD, who led the study. "Answering that question could help us understand why the disease occurs and point toward new ways to treat it."

Too much buzz

More than 8 million people worldwide are living with Parkinson's disease, a degenerative brain disease that causes tremors, slowed movement, stiff muscles, and problems walking and balancing.

Scientists know that a set of neurons that produce dopamine and support voluntary movements die in people with Parkinson's. Many lines of evidence also suggest that the activity of these cells actually increases with disease, both before and after degeneration begins. But whether this change in activity can directly cause cell death is poorly understood.

In the new study, Nakamura and his colleagues tackled this question by introducing a receptor specifically into dopamine neurons in mice that allowed them to increase the cells' activity by treating the animals with a drug, clozapin-N-oxide (CNO). Uniquely, the scientists 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," says Katerina Rademacher, a graduate student in Nakamura's lab and first author of the study. "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."

Within a few days of overactivating dopamine neurons, the animals' typical cycle of daytime and nighttime activities became disrupted. After one week, the researchers could detect degeneration of the long projections (called axons) extending from some dopamine neurons. By one month, the neurons were beginning to die.

Importantly, the changes mostly affected one subset of dopamine neurons-those found in the region of the brain known as the substantia nigra, which is responsible for movement control-while sparing dopamine neurons in brain regions responsible for motivation and emotions. This is the same pattern of cellular degeneration seen in people with Parkinson's disease.

A link to human disease

To gain insight into why overactivation leads to neuronal degeneration, the researchers studied the molecular changes that occurred in the dopamine neurons before and after the overactivation. They showed that overactivation of the neurons led to changes in calcium levels and in the expression of genes related 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."

Katerina Rademacher, First Author

When the researchers measured the levels of genes in brain samples from patients with early-stage Parkinson's, they found similar changes; genes related to dopamine metabolism, calcium regulation, and healthy stress responses were turned down.

The research did not reveal why activity of the dopamine neurons might increase with Parkinson's disease, but Nakamura hypothesizes that there could be multiple causes, including genetic and environmental factors. The overactivity could also be part of a vicious cycle initiated early in disease. As dopamine neurons become overactive, they gradually shut down dopamine production, which worsens movement problems. Remaining neurons work even harder to compensate, ultimately leading to cell exhaustion and death.

"If that's the case, it 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 says.