Plant Compound, Farnesol, Seen to Protect Neurons in Mouse Model
Farnesol, a natural compound of some herbs and fruits in commercial use, was seen to protect nerve cells in the brain and possibly restore some of these cells to health in multiple mouse models of Parkinson’s disease.
Specifically, the compound prevented the loss of dopamine-producing neurons — nerve cells that gradually die in Parkinson’s disease — in these mice, and reversed behavioral changes that mimic Parkinson’s symptoms in people.
“Our experiments showed that farnesol both significantly prevented the loss of dopamine neurons and reversed behavioral deficits in mice, indicating its promise as a potential drug treatment to prevent Parkinson’s disease,” Ted Dawson, MD, PhD, director of the Johns Hopkins Institute for Cell Engineering and one of the study’s lead authors, said in a press release.
The study, “PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease,” was published in Science Translational Medicine.
The death of dopaminergic neurons causes such motor symptoms as tremors and rigidity, as well as a progressive decline in cognitive abilities. Mutations in the PKRN gene contribute to this effect, as it codes for the parkin protein that is involved in the breakdown of other, unneeded proteins that are damaged or in excess.
Mutations affecting the parkin protein also lead to the accumulation of the parkin-interacting substrate (PARIS) protein, whose buildup promotes neurodegeneration in Parkinson’s. PARIS’ accumulation causes a decline in the production of PGC-1alpha, a protein that protects brain cells from the damaging reactive oxygen molecules that accumulate in the brain, a process known as oxidative stress.
Without PGC-1alpha, dopamine-producing neurons begin to malfunction and die. For this reason, “inhibiting PARIS accumulation might have therapeutic effect,” the researchers wrote.
A team in the U.S. and South Korea tested a large library of compounds for their ability to block PARIS. They found that farnesol — a compound commonly used in flavorings and perfume-making — inhibited PARIS by promoting what’s known as farnesylation — a type of protein modification that changes the shape of PARIS so that it can no longer impede PGC-1alpha production.
One model — that mimicking sporadic Parkinson’s — involved mice engineered to have brain fibrils, or clusters, of alpha-synuclein, the protein that accumulates in toxic clumps in the brains of patients. Another was the PARIS transgenic mouse model, in which the PARIS-coding gene was inserted into the midbrain of these mice via an adeno-associated virus, and a final model had a partial deletion of the PKRN gene.
To test if farnesol could protect the brain from damaging PARIS accumulation, animals in these models were fed either a farnesol-supplemented diet or a standard diet for one week.
They were then given a test of strength and coordination designed to match Parkinson’s progression. Mice on the farnesol-supplemented diet were seen to perform better than the standard diet groups.
“Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS” in the mice, the researchers wrote.
Specifically, farnesol-supplemented mice performed, on average, twice as well as did those on a standard diet.
Researchers then evaluated brain tissue from animals in the two diet groups, and found mice on the farnesol-supplemented diet had twice as many healthy dopamine-producing neurons as did standard diet mice. These mice also had about 55% more of the protective protein PGC-1alpha in their brain tissue.
Brain tissue samples from people with Parkinson’s disease also show lesser PARIS farnesylation relative to tissue from people without this disease, “suggesting that reduced farnesylation of PARIS may play a role” in Parkinson’s, the researchers wrote.
“Thus, farnesol may be beneficial in the treatment of PD [ Parkinson’s disease] by enhancing the farnesylation of PARIS and restoring PGC-1α activity,” they concluded.
While farnesol is naturally found in fruits such as peaches, vegetables like tomatoes and corn, and herbs such as lemon grass and chamomile, it is most frequent in commercial use, and the amount consumed through diet is not known.
As such, how much farnesol is needed to possibly be effective in treating this disease, while still safe to use in people needs both further preclinical study and clinical testing, the researchers added.