The link between pesticides and Parkinson’s had been based mainly on animal studies, with research demonstrating an increased risk of the disease among farmers, rural populations and others who are exposed to agricultural chemicals.
In the new study, American researchers used skin cells from Parkinson’s patients to determine whether there was a connection between the disease and exposure to pesticides.
Professor Stuart Lipton, of Sanford-Burnham Medical Research Institute in the United States, said: “For the first time, we have used human stem cells derived from Parkinson’s disease patients to show that a genetic mutation combined with exposure to pesticides creates a ‘double hit’ scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death.”
Research scientist Dr Frank Soldner said: “Exposing both normal and mutant neurons to pesticides – including paraquat, maneb and rotenone – created excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death.
“In fact, we observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels.”
Cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathway – called MEF2C-PGC1alpha – that normally protects neurons. The free radicals attacked the MEF2C protein, leading to the loss of function of this pathway that would otherwise have protected nerve cells from the pesticides.
Prof Lipton added: “Once we understood the pathway and the molecules that were altered by the pesticides, we used screening to identify molecules that could inhibit the effect of free radicals on the pathway.
“One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, our findings may have potential clinical implications for repurposing these drugs to treat Parkinson’s.”
While the study clearly shows the relationship between a mutation, the environment and the damage done to dopamine-containing neurons, it does not exclude other mutations and pathways from being important as well.
The team plans to explore additional molecular mechanisms that demonstrate how genes and the environment interact to contribute to Parkinson’s and other neurodegenerative diseases, such as Alzheimer’s and ALS.
Prof Lipton said: “In the future, we anticipate using the knowledge of mutations that predispose an individual to these diseases in order to predict who should avoid a particular environmental exposure. Moreover, we will be able to screen for patients who may benefit from a specific therapy that can prevent, treat, or possibly cure these diseases.”
The findings are published in the journal Cell.