Gene mutations may set stage for Parkinson’s after pesticide exposure
Study: Variations in lysosome genes may predispose people to develop disease
Variations in genes that are important for the function of lysosomes — the cellular equivalent of garbage disposals, which are responsible for removing molecular waste from cells — may help set the stage for the development of Parkinson’s disease in people who’ve had long-term pesticide exposure, a new study reports.
According to the researchers, such gene mutations linked to pesticides may predispose individuals to Parkinson’s.
“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,” Brent Fogel, MD, PhD, co-author of the study at the University of California Los Angeles, said in a university press release.
“This is a step forward in that direction,” Fogel said of the team’s findings.
The study, “Lysosomal genes contribute toParkinson’s disease near agriculture with high intensity pesticide use,” was published in npj Parkinson’s Disease.
Investigating Parkinson’s risk ‘in the setting of chronic high pesticide exposure’
The causes of Parkinson’s are not fully understood. Genetics likely play a role in influencing susceptibility to the neurodegenerative disease, but data also show that environmental factors, such as exposure to certain pesticides, can increase the risk of developing Parkinson’s.
Now, to better understand how genetics and pesticides may interact to affect Parkinson’s risk, a team of UCLA scientists analyzed data from the Parkinson’s, Environment, and Genes (PEG) study.
The PEG study is a multi-decade research effort tracking disease progression in more than 700 people with Parkinson’s who were exposed to pesticides. For this analysis, the researchers specifically assessed data from 386 patients who had detailed follow-up information available. Most of these patients were of white European descent — a fact the investigators noted as a limitation of the study, saying it highlights a need for further research in more diverse populations.
The analysis examined variations in 85 different genes. A few of these genes previously were linked to Parkinson’s risk, and all of them were associated with the function of lysosomes, which are cellular structures that act as so-called molecular garbage disposals to chop up cellular waste.
The researchers noted that “animal models and postmortem brain samples from patients have demonstrated lower levels of lysosomes and lysosomal-associated proteins” in Parkinson’s disease.
Essentially, in their work, the researchers looked for variants in these genes that were disproportionately more common among patients who had both been exposed to high levels of pesticides and were experiencing substantially fast disease progression — which implied that the genetic variations may be linked to a greater impact from pesticide exposure.
Their specific focus was on exposure to a combination of pesticides that are commonly used when growing cotton.
“We sought to identify genetic contributions to the risk of developing Parkinson’s disease in the setting of chronic high pesticide exposure,” the team wrote.
UCLA study involved population living in central California
The analysis ultimately identified 36 variants, or mutations, in 26 genes, according to the researchers. For some genes, multiple variants were identified.
More than two-thirds of the identified variants are in genes known to be related to lysosome function. Further molecular analysis indicated most of the variants reduced the genes’ functionality — implying they may set the stage for lysosome dysfunction.
“The specific role of the identified variants in modulating [Parkinson’s] 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 scientists wrote.
In a subsequent analysis, the team looked at data from another study called the Parkinson’s Progression Marker Initiative (PPMI). They sought to determine if any of the variants were more common in people with Parkinson’s than in those without the disease.
Of the 14 variants that were able to be assessed, only three were more common in Parkinson’s patients.
Because the PPMI mostly included people who aren’t regularly exposed to pesticides, this suggests “that the majority of variants we identified … contribute most to [Parkinson’s disease] risk when individuals are pesticide exposed,” the scientists concluded.
On a day-to-day basis, these [gene] 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.
The team called for further studies to assess how these genetic variants may affect Parkinson’s risk. But while more research is needed, according to Fogel, this result “supports the hypothesis that the genetic predisposition comes from minor changes in genes that are associated with lysosomal function.”
Essentially, “on a day-to-day basis, these variants are not having much of an impact,” Fogel said.
“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,” Fogel said, noting “this is called a gene-environment interaction.”
The researchers noted that “the study population resides in central California, a region known for its intense agriculture.”
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