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Parkinson's Disease Risk Variants Found in Pesticide-Exposed Patients


NEW YORK – A University of California, Los Angeles research team has tracked down Parkinson's disease-associated variants in pesticide-exposed individuals with the neurodegenerative disease, pointing to a potential two-hit effect on lysosomal function via genetic variation and environmental exposure.

"This work identifies new interactions between specific genes and environmental risks and further supports the contribution of both genetics and environmental factors in the development of Parkinson's disease," Brent Fogel, a neurology, clinical neurogenomics, and human genetics researcher at UCLA's David Geffen School of Medicine, said in an email, adding that the results "highlight the importance of a protein degradation pathway in the pathogenesis of Parkinson's disease."

For a study published in NPJ Parkinson's Disease on Thursday, Fogel and his co-authors used targeted panel sequencing to search for genetic risk variants in 757 individuals with Parkinson's disease. The participants were enrolled in the Parkinson's, Environment, and Genes study and lived in California's Central Valley — a region with a history of cotton crop agriculture and related long-term pesticide use.

"This patient cohort has been followed for decades with a detailed recording of environmental and clinical data, including exposure to agricultural pesticides," the authors wrote. "As agricultural pesticides are generally not applied individually but in combination, we focus on individuals who were exposed to a cluster of pesticides that are typically co-applied to cotton and related crops within the same growing season."

Since prior studies have suggested that lysosome activity has ties to Parkinson's disease development, the team's analyses largely focused on 85 genes linked to the function of the debris- and waste breakdown-related organelles. The variants detected were analyzed alongside data from the Genome Aggregation Database.

"The goal of this study was to assess whether exonic variants in genes known to be involved in lysosomal function are enriched in PD patients with this cotton cluster pesticide exposure," the authors wrote, noting that "we examined disease progression and focused on genetic variants in patients with the most progressive disease."

In the process, the investigators flagged three dozen rare variants falling in 26 genes, with some 72 percent of the suspicious variants turning up in genes with ties to autophagy and other forms of lysosomal function. All but five of the potential risk variants were classified as functionally deleterious by bioinformatics, they reported.

Lysosomes "are crucial for degrading proteins, including aggregated alpha-synuclein, organelles, such as damaged mitochondria, and other intracellular components through autophagy," the authors explained, noting that "as some pesticides may alter autophagy, a [two]-hit model to the lysosomal system where exposure would add to the genetic variant's impact is plausible." 

With the combined genetic results and environmental documentation, meanwhile, the team suggested that apparent risk variants in the pesticide-exposed participants with Parkinson's disease provide a look at genetic vulnerabilities that may be susceptible to certain environmental stressors.

"Better understanding of the genetic and environmental influences leading to Parkinson's disease can help understand who might be at the most risk for developing it, how persons with Parkinson's disease may have developed it, and suggest molecular targets for future therapies aided at reducing the risk of developing symptoms or prolonging onset," Fogel said. "This takes us one step closer to being able to prevent Parkinson's disease in the future."