Lysosomal Function Gene Variants of Parkinson Disease Enriched When Exposed to Pesticides

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A recent study showed the relationship between genes associated with lysosomal function and environmental exposure to pesticides in Parkinson disease.

Brent L. Fogel, MD, PhD, professor of neurology and human genetics at UCLA David Geffen School of Medicine

Brent L. Fogel, MD, PhD

Credit: UCLA

A newly published study in NPJ Parkinson’s Disease showed that variants in genes associated with lysosomal function, specifically autophagy, were enriched among patients with Parkinson disease (PD) exposed to agricultural pesticides. These findings suggest that altered lysosomal function may generate an underlying susceptibility for developing PD through pesticide exposure.1

In the gene enrichment analysis, investigators identified 36 variants in 26 genes in 757 patients with PD. Only 46% of the identified genes (n = 12) had multiple enriched variants and/or a single enriched variant present in multiple patients, representing approximately 61% (n = 22) of the observed variants in the cohort. Notably, 72% of the enriched variants were reported in genes that contributed to lysosomal function, particularly autophagy, and 86% of the variants in the cohort were bioinformatically deemed functionally deleterious by investigators (n = 31).

Top Clinical Takeaways

  • Variants in genes linked to lysosomal function may contribute to Parkinson disease (PD) susceptibility, especially when exposed to agricultural pesticides.
  • The study suggests a gene-environment interaction in PD development, emphasizing the importance of understanding both genetic and environmental factors.
  • Limitations in the study highlight the need for further research to elucidate the complex interplay between genetics, environmental exposures, and disease risk.

"We examined genetic data from nearly 800 California Central Valley residents with PD, many of whom had long-term exposure to 10 pesticides used on cotton crops for at least a decade prior to developing the disease, and looked for enrichment of genetic variants in patients with high exposure to pesticide use compared with a representative sample of the general population," senior author Brent L. Fogel, MD, PhD, professor of neurology and human genetics at UCLA David Geffen School of Medicine, told NeurologyLive®.

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Investigators assessed the frequency of variants in lysosomal function genes among participants from the Parkinson’s, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. In this analysis, researchers screened patients with PD, primarily of White European/nonHispanic ancestry (75%), for variants using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Additionally, investigators prioritized enriched exonic variants by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity.

"We found that variants in these genes were enriched in patients with more severe PD who also had higher exposure to pesticides. These genetic variants appeared to be deleterious to proteins that function in lysosomes, cellular compartments that break down waste and debris, thought to be associated with the development of PD," Fogel, who also serves as the director of the Neurogenetics Clinic and the UCLA Clinical Neurogenomics Research Center, said. "This suggests that disruption of lysosomal activity may be underlying the development of PD in people with pesticide exposure."

In an additional analysis, investigators assessed whether any of the identified prioritized variants were enriched in a cohort of 496 patients with PD and 192 healthy controls from the Parkinson’s Progression Marker Initiative (PPMI)3, a large-scale cohort not known for a high level of pesticide exposure. Researchers noted that they could not evaluate 61% of the variants not presented in the PPMI cohort (n = 22). Of the 39% remaining ones (n = 14), 3 were enriched in the PPMI PD cohort (8%) which represented 2 variants observed in multiple PEG participants in the GALC (n = 7) and TSC1 (n = 5) genes, as well as the highest ranked FBXO7 variant based on the calculated disease severity and pesticide exposure score. Notably, the remaining 11 variants (31%) were not enriched in PPMI cohort.

"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 PD. These results also highlight the importance of a protein degradation pathway in the development of PD," Fogel added.

All told, the small sample size of the cohort may have led to a skewed representation toward European descent and potential biases in variant enrichment. The absence of a racially matched population control and limited assessed genes may have further constrained the analysis's scope. In addition, inability to examine variants not presented in the gnomAD database and discern of specific contribution of gene-pesticide interactions versus other genetic factors may pose another limitation. Although authors attempted to evaluate potential additive effects of enriched variants, uncertainties regarding their independent roles remain. Thus, authors noted future research that incorporates broader genomic sequencing methods and model systems may offer insight into these complexities.

“Better understanding of the genetic and environmental influences leading to PD can help understand who might be at the most risk for developing it, how patients with PD may have developed it, and suggest molecular targets for future therapies aimed at reducing the risk of developing symptoms or prolonging onset. This takes us one step closer to being able to predict who might be most at risk to develop PD and how to prevent PD in the future,” Fogel said.

REFERENCES
1. Ngo KJ, Paul KC, Wong D, et al. Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use. npj Parkinsons Dis. 2024;10(87). doi:10.1038/s41531-024-00703-4
2. Houston W. Genetic variations may predispose people to Parkinson’s disease following long-term pesticide exposure, study finds. News Release. Published April 25, 2024. Accessed April 25, 2024. https://www.uclahealth.org/news/genetic-variations-may-predispose-people-parkinsons-disease
3. Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol. 2011;95(4):629-635. doi:10.1016/j.pneurobio.2011.09.005
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