The hallmark symptoms of Parkinson’s disease are motor symptoms that include shaking hands and slowness of movement, but specialists still do not entirely understand what causes this disease. Newly published research may now overturn prevailing notions about key Parkinson’s mechanisms.

Motor symptoms in Parkinson’s disease may be due to brain changes that take place earlier than experts had previously thought.
According to official estimates, in 2020, approximately 930,000 people aged 45 years or older in the United States will be living with Parkinson’s disease.

Despite the large number of people who live with this condition, researchers are still unsure exactly what causes it, and, to date, they have found no way of reversing it.

The primary symptoms of Parkinson’s disease affect movement and include shakiness, slowness of movement, and limb rigidity.

These motor symptoms can seriously affect a person’s quality of life, so specialists have put a lot of work into finding ways of lessening their effects.

So far, the prevalent view among Parkinson’s disease specialists has been that the motor symptoms occur when dopaminergic neurons — the brain cells that synthesize the chemical messenger dopamine — start dying off abnormally.

Therefore, to try to offset motor symptoms, doctors may prescribe people with Parkinson’s disease a drug called levodopa (or L-DOPA), which helps boost the brain’s reserve of dopamine.

However, the long-term use of L-DOPA can lead to serious side effects, including erratic, involuntary movements.

But what if motor symptoms do not start with the death of dopaminergic neurons? If this were the case, it could change how researchers and medical practitioners understand Parkinson’s disease and the best way of treating it.

Researchers find new mechanism
A new study may now overturn existing notions regarding the cause of motor symptoms. Lead researchers C. Justin Lee, Ph.D., Hoon Ryu, Ph.D., and Sang Ryong Jeon worked with colleagues from the Institute for Basic Science in Daejeon and both the Korea Institute of Science and Technology and the Asan Medical Center in Seoul — all in South Korea.

The research, which appears in the journal Current Biology, found that symptoms of Parkinson’s disease appear before the premature death of dopaminergic neurons.

In their study, the investigators worked with mouse models of Parkinson’s disease and also analyzed brain samples from both healthy people and people with Parkinson’s.

They found that before the dopaminergic neurons die off, they stop functioning — that is, they stop correctly synthesizing dopamine — and this sets off the symptoms associated with Parkinson’s disease.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of [Parkinson’s disease]. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” says Lee.

“The neuronal death ruled out any possibility to reverse [Parkinson’s disease].” However, he notes, “[s]ince dormant neurons can be awakened to resume their production capability, this finding will allow us to give [Parkinson’s disease] patients hopes to live a new life without [Parkinson’s disease].”

Looking at the mouse models of the condition, the researchers saw that astrocytes — star shaped, non-neuronal cells — in the brain started increasing in number when neurons in their vicinity began dying off.

At this point, a key chemical messenger called GABA also starts increasing in the brain, reaching an excessive level and stopping dopaminergic neurons from producing dopamine, though not killing them.

The researchers confirmed that this process occurs not just in animal models, but also in the brains of people with Parkinson’s disease.

Hope for better treatments
However, the researchers also found that there is a way to restore the function of affected dopaminergic neurons by stopping astrocytes from synthesizing GABA. Doing this, they saw, also significantly decreased the severity of motor symptoms associated with Parkinson’s disease.

Further experiments in rats revealed another way of restoring function in dopaminergic neurons. The researchers inhibited dopamine synthesis in these neurons in otherwise healthy rat brains by using optogenetic tools — technology that uses light to control the activity of living cells.

This action induced Parkinson’s-like motor symptoms in the rats. But when the researchers used optogenetic tools once more, this time to restore function in the dormant dopaminergic neurons, the Parkinson’s-like symptoms decreased in severity.

“This research refutes the common belief that there is no disease-modifying treatment for [Parkinson’s disease] due to its basis on neuronal cell death,” emphasizes Ryu. “The significance of this study lies in its potential as the new form of treatment for patients in early stages of [Parkinson’s disease],” the researcher adds.

In the future, argues the research team, these findings may lead to better ways of treating Parkinson’s disease — ways that may reverse some of the damage to important brain mechanisms.

“So far, it had been firmly believed that idiopathic [Parkinson’s disease] is caused by the death of dopaminergic neurons in [the] substantia nigra [a structure of the brain],” notes Jeon.

“However, this research demonstrates that functional inhibition of dopaminergic neurons by surrounding astrocytes is the core cause of [Parkinon’s disease]. It should be a drastic turning point in understanding and treating [Parkinson’s disease] and possibly other neurodegenerative disease as well.”

Sang Ryong Jeon