- A progressive loss of dopamine-producing nerves in the brain causes the difficulties with movement and cognition that characterize Parkinson’s disease.
- A study has found that farnesol, which people use in perfumery and is a component of many essential oils, preserves dopamine nerves in a mouse model of Parkinson’s.
- Researchers have not yet determined the safety and efficacy of farnesol as a treatment in humans.
In Parkinson’s, dopamine-producing neurons (nerves) in a part of the brain called the substantia nigra progressively die off.
Dopamine neurons are essential for movement and cognition, so their gradual loss over several years causes worsening symptoms, such as tremors, muscle rigidity, difficulty walking, and dementia.
There are currently no proven therapies to delay or prevent the progression of Parkinson’s.
Drugs such as L-DOPA boost dopamine levels in the brain and improve dopamine nerve signaling, which helps alleviate motor symptoms. These treatments do not slow the progressive loss of dopamine nerves, however.
So the discovery by researchers of a compound that prevents the death of dopamine neurons in a mouse model of Parkinson’s disease could herald a step change in treatment.
The compound, called farnesol, occurs naturally in plants and is a component of several essential oils, including citronella, lemongrass, and balsam. It has long featured as an ingredient in the manufacture of perfumes. The compound is also widespread in animal tissues.
“Parkinson’s is what happens when dopamine-producing cells in the brain die, so this study is important as it highlights a new pathway that could target and protect these brain cells in a person with Parkinson’s,” said Prof. David Dexter, Ph.D., associate director of research at the charity Parkinson’s UK, who was not involved in the study.
“[T]he need for a new treatment [that] could slow or stop Parkinson’s in its tracks has never been more urgent,” Prof. Dexter told Medical News Today.
“Designing more potent drugs replicating the action of this natural compound — farnesol — would be the next steps for researchers to progress this into clinical trials and potentially hold the key for a groundbreaking new treatment,” he said.
The new research, led by scientists at Sungkyunkwan University School of Medicine in Suwon, South Korea, and Johns Hopkins University School of Medicine in Baltimore, MD, appears in Science Translational Medicine.
The researchers began by screening a large library of drugs to find a compound that inhibits a protein called PARIS, which is implicated in the death of dopamine neurons in Parkinson’s.
PARIS slows down the manufacture of another protein, PGC-1 alpha, which shields brain cells from highly reactive oxygen molecules.
If levels of PGC-1 alpha are low, the reactive molecules eventually kill the cells.
The screening process identified farnesol as a potent inhibitor of PARIS. Importantly, people can take the drug orally, and it can cross the blood-brain barrier to protect brain cells.
Farnesol chemically alters PARIS in a process known as farnesylation. The researchers were intrigued to discover from postmortem studies that levels of farnesylated PARIS were lower in the substantia nigra of people with Parkison’s compared with controls.
This finding suggests that reduced farnesylation of PARIS contributes to the death of dopamine neurons in Parkinson’s.
To investigate whether farnesol can protect neurons, the researchers fed mice either a regular diet supplemented with farnesol or the regular diet alone for 1 week.
They then injected fibrils of a misfolded protein called alpha-synuclein — a hallmark of Parkinson’s — into the animals’ brains.
The mice that had eaten the farnesol-supplemented diet went on to perform twice as well on standard tests of strength and coordination compared with the mice that ate an ordinary diet.
The researchers subsequently discovered that the mice on the farnesol diet had twice as many healthy dopamine neurons in their brains.
The brains of the mice that ate a normal diet contained about 55% less of the protective protein PGC-1 alpha than those of the mice with the farnesol-supplemented diet.
In test-tube experiments, the scientists found that when farnesol binds to PARIS, it changes the other protein’s shape. This prevents PARIS from interfering with the production of PGC-1 alpha.
“[T]his is kind of like putting a cover over a light switch to keep PARIS from turning off the cellular switch controlling production of PGC-1 alpha,” explained James C. Beck, Ph.D., chief scientific officer at the Parkinson’s Foundation, who was not involved in the study.
He said that scientists have recognized PGC-1 alpha for some time as a potential target for new Parkinson’s disease drugs because high levels can protect dopamine neurons.
“There are several ways to activate PGC-1 alpha, but farnesol is definitely unique,” he told MNT.
Although other drugs under development stimulate PGC-1 alpha directly, he said, this will not help if levels of the protective protein are too low.
In contrast, farnesol works by boosting the production of PGC-1 alpha, ensuring that enough is available to prevent dopamine neurons from dying.
The scientists behind the new research are planning a clinical trial of farnesol in patients with Parkinson’s disease.
“Issues such as formulation and dose need to be worked out,” said co-senior author Ted Dawson, M.D., Ph.D., director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at Johns Hopkins University School of Medicine.
“Once these are settled, then we hope a clinical trial can move forward,” he told MNT.