Decades of research have linked pesticide exposure to Parkinson’s disease (PD) risk, and researchers have sought to understand why some individuals with high exposure develop the disorder while others do not. A study by University of California, Los Angeles (UCLA) scientists has now found that certain rare genetic variants might help to explain the relationship between pesticide exposure and risk of Parkinson’s disease. The team analyzed genetic data from hundreds of patients with PD who had long-term exposure to pesticides typically used on cotton crops, in comparison with PD patients who had more typical environmental exposure to pesticides. Their analyses identified 36 variants in 26 genes that linked pesticide exposure to PD. Most of the variants were found in genes associated with lysosomal function.

Brent Fogel, MD, PhD, professor of neurology and human genetics, suggested that while the specific interactions between pesticides and the expression of the genetic variants identified requires further study, the results indicate that in someone with the relevant variants, long-term exposure to the cotton pesticides evaluated in the study could lead to the build up of toxic compounds due to alterations of the cells’ ability to break down damaged proteins and organelles—a process known as autophagy—and thus lead to Parkinson’s disease.

Fogel is corresponding author of the team’s published paper in npj Parkinson’s Disease, which is titled “Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use.” In their paper the teams concluded, “… this study supports a relationship between genes associated with lysosomal function and environmental exposure to pesticides in the development and progression of PD.”

“Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease,” the authors wrote. “While the etiology of sporadic PD is certainly multifactorial and includes both genetic and environmental factors, extensive genetic studies have resulted in the discovery of several gene mutations that can cause familial PD or polymorphisms that can alter risk and have provided us with some valuable insight into the pathogenesis of the disease.” However, they noted, genetics alone only accounts for the minority of cases and cannot explain the increasing incidence of PD.

Epidemiologic studies have long shown pesticide exposure to be a risk factor for PD, they suggested. To better understand genetic factors influencing PD risk associated with pesticide exposure, the team turned to a well-documented cohort of 757 PD patients enrolled in the Parkinson’s, Environment, and Genes (PEG) study.

The team analyzed genetic data from nearly 800 Central Valley (California) residents with Parkinson’s disease, many of whom had long-term exposure to 10 pesticides used on cotton crops for at least a decade prior to developing the disease. Some patients had been exposed as far back as 1974. “This patient cohort has been followed for decades with a detailed recording of environmental and clinical data, including exposure to agricultural pesticides,” the scientists explained. “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.”

The researchers examined the study participants’ genetic makeup for rare variants in genes associated with the function of lysosomes, cellular compartments that break down waste and debris, and which it has been thought may be associated with the development of Parkinson’s disease. They looked for enrichment of variants in patients with high exposure to pesticide use compared to a representative sample of the general population. Their analyses focused on a panel of 85 genes associated with PD risk and/or lysosomal function.

“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 investigators further explained. To identify those variants with the greatest potential impact, they looked at disease progression, and identified genetic variants in patients with the most progressive disease. “To identify genetic variants most associated with disease in the context of pesticide exposure, for each variant we examined the magnitude of pesticide exposure and the severity of disease progression across the cohort,” they stated.

The team found that variants in these genes were enriched in patients with more severe Parkinson’s disease who also had higher exposure to pesticides. Of the 36 prioritized enriched genetic exonic variants in 26 genes, 26 (72%) were found to be related to lysosomal function. The identified genetic variants appeared to be deleterious to protein function, suggesting that disruption of lysosomal activity may be underlining the development of Parkinson’s disease combined with pesticide exposure.

Previous studies have shown that altered autophagy can result in a build-up of alpha synuclein, which is abundant in the brain and in neurons. As the protein builds up, it forms clumps known as Lewy bodies that are a pathological hallmark of Parkinson’s disease. Lysosomes, which are intracellular organelles that contain hydrolytic enzymes, are crucial for degrading proteins, including aggregated alpha synuclein. “Multiple lines of evidence implicate impaired autophagy-lysosomal pathways in Parkinson’s disease,” the investigators stated. “Animal models and postmortem brain samples from patients have demonstrated lower levels of lysosomes and lysosomal-associated proteins (e.g. LAMP1) along with an accumulation of autophagosomes in PD.”

Fogel said that the newly reported study results support the hypothesis that genetic predisposition comes from minor changes in genes that are associated with lysosomal function. “On a day-to-day basis, these variants are not having much of an impact. But under the right stress, such as exposure to certain pesticides, they can fail and that could, over time, lead to the development of Parkinson’s disease. This is called a gene-environment interaction.” The authors added, “The specific role of the identified variants in modulating PD risk and disease progression in the setting of pesticide exposure is unknown but it is reasonable to assume that it may involve impairment of protein function and disruption of specific lysosomal pathways.”

The findings build on decades of research by UCLA Health investigators and co-authors Jeff Bronstein, MD, PhD, and Beate Ritz, MD, PhD, into the associations between pesticide exposure and Parkinson’s disease risk in the Central Valley. Study co-lead author Kimberly Paul, PhD, assistant professor of Neurology at UCLA, said Parkinson’s disease is the fastest growing neurodegenerative disease in the world. While an increase in the number of new patients is expected given the large aging population in the U.S., the rate of new Parkinson’s disease patients is outpacing the rate that is expected from aging alone, Paul said.

Paul said the newly reported study results raise the question of whether there are other genetic variants that may be altering the susceptibility to Parkinson’s disease among this population, including other biological pathways affected by different types of pesticides. “These patients were susceptible somehow and if we can figure out why they were susceptible, maybe we can act on those pathways,” Paul added.

Fogel added, “There are data for a lot of common disorders suggesting that environmental influences impact the development of these diseases, but we don’t yet have a good way of measuring that impact or determining who is specifically at risk. This is a step forward in that direction.”

Noting limitations of their research, the team concluded, “Further study of these genes and variants in conjunction with environmental exposures could aid the identification of novel mechanisms for PD through gene-environment interactions and eventually lead to better methods of prevention of PD in individuals exposed to pesticides or improved disease treatments.”

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