Exposure to the commonly used pesticide ziram may be linked to Parkinson’s disease development by inducing α-synuclein expression and damages to the dopaminergic neurons. The findings have been published in the journal Environmental Health Perspectives in the study “Neurotoxicity of the Parkinson’s Disease associated Pesticide Ziram is Synuclein-Dependent in Zebrafish Embryos.”
Parkinson’s disease is a neurodegenerative disease that affects millions of individuals worldwide. Its cause is still not fully understood. Although the genetics of Parkinson’s disease have been extensively studied, only a small percentage of Parkinson’s patients develop the disease due to genetic causes, suggesting that environmental factors may play a major role.
Studies have demonstrated that exposure to pesticides is associated with an increased risk of developing Parkinson’s. The dithiocarbamate fungicide ziram, in particular, which is commonly used in heavily agricultural areas, has been shown to increase this risk up to sixfold, possibly by damaging the dopaminergic neurons, which are responsible for dopamine production. However, the molecular mechanisms that lead to such damages are unknown.
Now, UCLA researchers have developed a zebrafish model for Parkinson’s, found to have selective loss of the dopaminergic neurons and impaired swimming behavior when exposed to ziram.
Ziram had already been shown to increase the levels of α-synuclein, a protein that forms aggregates known to be toxic for dopaminergic neurons. Consistently, the investigators found that γ1 synuclein, the functional homologue of α-synuclein in zebrafish, also formed neuronal aggregates with a similar neurotoxicity. Depleting the γ1 synuclein from the zebrafish rendered them resistant to the ziram-induced toxicity in the dopaminergic neurons.
The researchers also attempted to protect the zebrafish from ziram toxicity with a drug called CLRO1, known to break down α-synuclein aggregates in humans. Similarly, CLRO1 also prevented γ1 synuclein aggregation, reducing ziram’s toxicity in zebrafish. These findings suggest that targeting α-synuclein could stop or slow Parkinson’s progression in most patients.
“Getting rid of the protein genetically or breaking up the aggregates with this drug protected against ziram toxicity,” study lead author Jeff Bronstein, a professor of neurology and director of movement disorders at the David Geffen School of Medicine at UCLA, said in a press release.
“This is important — it establishes that environmental toxins work on same pathway that is in play in those genetically disposed to Parkinson’s. Most important, we can use drugs being developed now on patients who get Parkinson’s because of ziram exposure,” Bronstein said.