Awakening Dormant Neurons Could Provide Disease-modifying Parkinson’s Treatment, Early Study Suggests

Together with dying nerve cells, dormant neurons also may be at the root cause of Parkinson’s disease, according to a recent study in animal models.

Reawakening these neurons by targeting a type of brain cells called astrocytes can restore dopamine production in the brain and reverse Parkinson’s motor symptoms, the study found. These findings could lead to a potential new disease-modifying treatment, especially at the early stages of Parkinson’s.

The study, “Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease,” was published in the journal Current Biology.

Despite its prevalence and debilitating consequences, current medical therapy for Parkinson’s relies on alleviating symptoms. Research investigating ways of modifying the disease or reversing its symptoms is scarce, based on the firm belief that Parkinson’s is caused by the irreversible death of nerve cells — also called neurons — in a region of the brain called the substantia nigra.

In this brain region, nerve cells known as dopaminergic neurons are responsible for producing the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate. Dopamine plays a key role in motor function control and also is involved in behavior and cognition, memory and learning, sleep, and mood.

Levodopa, a mainstay of Parkinson’s treatment, works by supplying extra dopamine to the brain. However, it only alleviates motor symptoms and does not alter the disease course. Moreover, its long-term use can cause serious side effects, including involuntary, erratic, and writhing movements.

Now, a team of Korean researchers have discovered additional clues about the underlying mechanisms of Parkinson’s that may offer hope for the development of disease-modifying treatments that could reverse the condition.

Using mouse and rat models of Parkinson’s, they found that the motor abnormalities that mark the disease begin earlier than was previously thought. They are triggered when dopaminergic neurons in the substantia nigra are still alive but in a dormant state, unable to produce dopamine.

However, what holds the key to that dormant state is another type of cells called astrocytes, star-shaped cells present in the brain and spinal cord that play important roles in the protection and regulation of the nervous system.

When neurons die, nearby astrocytes react by proliferating, and start to release an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA) at excessive levels. This puts neighboring neurons “on hold,” suspending their production of dopamine.

GABA prevents the neurons from firing electrical impulses and causes them to stop making an enzyme, called tyrosine hydroxylase, that’s essential for the production of dopamine. In effect, GABA puts the neurons into a dormant, or sleeping state.

One of the most important discoveries of the study was that surviving dormant neurons could actually be “awakened” from their “sleeping” state and rescued to alleviate motor symptoms.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” C. Justin Lee, PhD, the study’s corresponding author, said in a press release.

“The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD,” Lee added.

Treatment with two different compounds that block GABA production in astrocytes, called monoamine oxidase-B, or MAO-B, inhibitors, was sufficient for neurons to recover the enzymatic machinery necessary to produce dopamine, the study found. This significantly alleviated Parkinson’s motor symptoms in the study animals.

In fact, the MAO-B inhibitors used for the study — selegiline (brand names Eldepryl, Carbex, Zelapar, among others), and safinamide (brand name Xadago) — are already prescribed to Parkinson’s patients as an add-on therapy to levodopa. They are believed to prevent the break down of dopamine in the brain.

Importantly, the existence of dormant neurons was observed in the brains of human patients. Analysis of postmortem brains of individuals with mild and severe Parkinson’s had a significant population of dormant neurons surrounded by numerous GABA-producing astrocytes.

The researchers hope that “awakening” neurons using MAO-B inhibition could be an effective disease-modifying therapeutic strategy for Parkinson’s, especially for patients in the early stages of the disease. At that time, inactive, yet live dopaminergic neurons are still present.

Although the results from several clinical trials have cast doubt on the therapeutic efficacy of traditional MAO-B inhibitors, researchers say they have recently developed a new inhibitor, KDS2010. KDS2010 effectively inhibits astrocytic GABA production with minimal side effects in Alzheimer’s animal models and also could be effective for alleviating Parkinson’s motor symptoms, the investigators said.

“This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death,” said Hoon Ryu, PhD, a researcher at KIST Brain Science Institute, in South Korea, and one of the senior authors of the study.

“The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD,” Ryu said.

The fact that inhibition of dopaminergic neurons by surrounding astrocytes is one of the core causes of Parkinson’s should be a “drastic turning point” in understanding and treating not only Parkinson’s but also other neurodegenerative diseases, added Sang Ryong Jeon, MD, PhD, also a researcher at KIST and a study co-author.