Farnesol, an antimicrobial compound found in herbs, fruits, and fungi prevents and reverses brain damage linked to Parkinson’s disease (PD), an international team led by scientists at Johns Hopkins University School of Medicine claims, based on mouse studies.

Tremors, muscle rigidity, confusion, and dementia—the hallmarks of PD—are caused by the loss of neurons that secrete the neurotransmitter molecule dopamine that regulates mood, movement, and cognition. The loss of dopamine neurons in patients with PD is particularly apparent in a region of the midbrain called substantia nigra, Latin for “black substance,” that is darker than surrounding regions because of high levels of melanin in dopamine neurons.

The researchers showed, farnesol, commonly used in flavorings and perfume-making, prevents the loss of dopamine-releasing neurons in mice brains by inactivating a protein called PARIS (parkin-interacting substrate). Autopsy on human brains of PD patients and models of PD shows an increase in PARIS levels due to the inactivation of an enzyme called parkin that degrades PARIS.

The findings that detail how the researchers identified farnesol’s potential by screening a large library of drugs to find those that inhibit PARIS, were reported in the journal Science Translational Medicine, in the article titled, “PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease.” The authors believe farnesol could guide development of new PD interventions that target PARIS.

Financial support for the work came from grants from the JPB Foundation, the Cure Parkinson’s Trust, the Bachmann-Strauss Dystonia and Parkinson Foundation, the Adrienne Helis Malvin Medical Research Foundation, the Diana Helis Henry Medical Research Foundation, and the National Institutes of Health. Two patents are linked to the study.

PARIS and Farnesyltransferase, the enzyme that enables farnesylation. [Source: Johns Hopkins School of Medicine]
“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,” said Ted Dawson, MD, PhD, director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine.

The buildup of PARIS slows down the synthesis of a protective protein, PGC-1alpha that shields brain cells from damaging reactive oxygen molecules—metabolic products that accumulate over time if not actively cleared from the system. When PGC-1alpha is absent or dysfunctional, dopamine neurons die, unable to withstand high levels of reactive oxygen molecules.

The researchers fed mice either a farnesol-supplemented diet or a regular mouse diet for one week to establish whether farnesol protects brains from the effects of PARIS accumulation.

Toward this goal, the researchers used several mouse models of PD—transgenic mice that produced excessive amounts of PARIS, mice injected with PARIS contained adeno-associated virus in the midbrain, adult mice with selective inactivation of parkin in their brains, and a mouse model of sporadic PD generated by the injection of the fibrillar protein, alpha-synuclein.

In these different models, the researchers showed that mice fed farnesol performed better on strength and coordination tests designed to detect the progression of PD.

When the researchers compared brain tissue of PD mice in the farnesol fed and control groups, they found that the mice fed a farnesol-supplemented diet had twice as many healthy dopamine neurons than control mice. The farnesol-fed mice also had approximately 55% more PGC-1alpha in their brains.

In biochemical experiments, the researchers confirmed that farnesol binds to PARIS in a process called farnesylation, changing the protein’s shape so that it can no longer prevent PGC-1alpha production.

While farnesol is naturally produced, the compound is also synthetically produced and commercially used. Amounts people get through diet is unclear. The researchers caution that safe doses of farnesol for humans have not yet been determined. Carefully controlled clinical trials will be needed to determine safe doses. Dawson and his team hope farnesol can someday be used to develop treatments that prevent or reverse brain damage in PD.