Cases of Parkinson’s disease have doubled in the last 25 years, according to figures from the World Health Organization. For decades, the scientists have investigated what triggers this disorder to mitigate its symptoms and anticipate its onset. Now, a series of experimental therapies are laying the groundwork for potentially reversing the condition, which affects nearly 10 million people worldwide and can generate costs of approximately $10,000 per patient per year, when considering direct and indirect medical expenses.
Parkinson’s disease is a degenerative neurological disorder in which cells that produce dopamine in the brain die, causing symptoms such as tremors, muscle stiffness, slowness of movement, and alterations in balance. So far there is no cure, and treatments are limited.
Kay Double, a professor at the University of Sydney’s School of Medical Sciences, has been researching the biological mechanisms underlying this disease for more than a decade, with the aim of finding ways to slow or even halt its progression.
In 2017, he led a study that identified for the first time an abnormal form of a protein called SOD1 in Parkinson’s patients. Under normal conditions, this protein acts as an antioxidant enzyme, protecting brain cells from damage caused by free radicals, highly reactive molecules that contain oxygen and can deteriorate cells if not properly neutralized. Free radicals are produced by natural bodily processes as well as by external factors, like diet, smoking, and exposure to pollution.
In people with Parkinson’s disease, SOD1 suffers alterations that prevent it from fulfilling its protective function, with it instead accumulating in the brain and causing neuronal damage, according to the findings of Double’s team.
Based on these results, the team then conducted further research, with results suggesting that copper supplementation in the brain could be an effective way to slow and even reverse the symptoms of Parkinson’s (copper is crucial to SOD1’s function). To test this hypothesis, they evaluated the efficacy of a drug called CuATSM, designed to cross the blood-brain barrier and deliver copper directly to brain tissue.
This experiment, written up and published in Acta Neuropathologica Communications, was divided into two phases. The first was to determine the optimal dose of the drug to induce a response in the brain. To find this, CuATSM was administered daily for three weeks to 27 eight-week-old wild-type mice, with concentrations of copper and other metals then measured in the mice’s tissues. This revealed that 15 milligrams per kilogram was the ideal dose to effectively increase the levels of copper in the brain.
In the second stage, this dose was applied to 10 mice genetically modified to develop Parkinson’s-like symptoms. The animals were divided into two groups: one received CuATSM daily for three months, while the other received a placebo without the active ingredient.
The results showed that the mice treated with the placebo experienced a deterioration in their motor skills. In contrast, those that received the copper supplement showed no alterations in their movement. It appears the treatment corrected the dysfunctions of SOD1 and restored its protective properties. In the mice receiving the copper treatment, dopamine neurons were preserved in an area of the brain called the substantia nigra, an area essential for the control of movement, coordination, learning, and certain cognitive functions.
“All of the mice we treated showed dramatic improvement in their motor skills. The results exceeded our expectations and suggest that, after further study, this therapeutic approach could slow the progression of Parkinson’s in humans,” says Double.
But experts caution that Parkinson’s is a complex condition that will likely require multiple combined interventions. A single treatment may have limited effect, but its efficacy may be enhanced by integrating it with other therapeutic approaches.
In that context, Double’s team’s findings could be complemented by recent research from Stanford University focused on restoring communication between neurons in a subtype of Parkinson’s linked to mutations in the gene responsible for producing an enzyme called LRRK2.
In these cases, the mutation causes hyperactivity of the enzyme, altering the structure of brain cells and disrupting signaling between dopaminergic neurons and those in the striatum, a deep brain region related to movement, motivation, and decision-making.
It is estimated that about 25 percent of Parkinson’s cases are genetic in origin, and the LRRK2 mutation is one of the most frequent. The team led by Stanford neuroscientist Suzanne Pfeffer proposed that inhibiting the excessive activity of this enzyme could stabilize symptoms, especially if detected in early stages. The goal was to regenerate primary cilia, antenna-like structures that enable communication between cells.
The hypothesis was tested in mice genetically modified to exhibit LRRK2 hyperactivity and early symptoms of the disorder. For two weeks, these animals were administered with a compound called MLi-2, which binds to the enzyme and reduces its activity.
In this first test, no relevant changes were observed, which the researchers attributed to the fact that the examined neurons and glia—another type of cell in the nervous system, which support neurons—were already mature and were not in the cell division phase.
However, a review of the scientific literature revealed that, even if mature, certain neurons can regenerate their primary cilia depending on their sleep-wake cycles. “The findings that other nonproliferative cells can develop cilia made us think that the inhibitor still had therapeutic potential,” Pfeffer explains.
The team then decided to extend the treatment to three months. After this period, they found that the percentage of neurons and glial cells in the striatum with primary cilia was comparable to that of healthy mice without the genetic mutation.
This restoration of cellular structures made it possible to reactivate communication between dopaminergic neurons and the striatum. As a result, neurotransmitters affected by the LRRK2 protein induced the production of neuroprotective factors at levels similar to those of a healthy brain, something that had been diminished as a result of LRRK2 hyperactivity. In addition, density markers of dopaminergic nerve endings were doubled, suggesting a possible recovery of previously damaged neurons.
“These findings suggest that it is not only possible to stabilize the disease, but also to improve the condition of patients. This therapeutic approach has great potential to restore neuronal activity in Parkinson’s-affected circuits. There are currently several ongoing clinical trials with LRRK2 inhibitors, and we hope that these results in mice can be translated to humans,” says Pfeffer.
The authors stress that, to maximize the effectiveness of this treatment, it is essential to identify early symptoms, which can occur up to 15 years before the characteristic tremors. The hope is that people with the LRRK2 mutation will be able to start treatment early. The next step would be to assess whether other Parkinson’s variants, not associated with this genetic mutation, could also benefit from this strategy.
It is estimated that the number of Parkinson’s cases worldwide could exceed 25 million by 2050, which would represent a 112 percent increase over 2021 figures, according to projections published in the British Medical Journal. Although these estimates are not definitive, the scientific community warns that they reflect a growing challenge for public health systems. For this reason, developing therapies capable of mitigating, stabilizing, and even reversing the progression of the disease is a global priority.
This story originally appeared on WIRED en Español and has been translated from Spanish.
