In a recent study published in npj Parkinson's Disease, researchers examined genetic characteristics that influence the risk of Parkinson's disease (PD) due to pesticide exposure.
Study: Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use. Image Credit: Mariana Serdynska/Shutterstock.com
Background
PD is a complicated disorder caused by hereditary and environmental causes. Abnormal protein homeostasis involving altered autophagy is critical to PD pathophysiology.
Recent research has highlighted the role of autophagic function in PD etiology, with mutations in the glucosylceramidase beta (GBA1) gene increasing the likelihood of developing PD.
About the study
In the present study, researchers investigated the genetic contributions to PD risk in the presence of chronic pesticide exposure.
Researchers investigated exonic variations in genes related to lysosomal function and their probable influence on PD patients. They used a unique amplicon panel to screen 757 Parkinson’s, Environment, and Genes (PEG) study participants, predominantly of white European or non-Hispanic descent.
They conducted a gene-environment analysis to examine uncommon variations in 85 genes linked to Parkinson’s disease risk and lysosomal function in the presence of pesticides often used to treat cotton.
The team assessed variant enrichment using the Genome Aggregation Database (gnomAD) by comparing known variants to their corresponding self-identified populations, prioritizing enriched exonic variants based on cotton pesticide exposures and illness progression severity in 386 individuals.
They compared variation frequencies to most racially comparable White European and non-Hispanic populations in the gnomAD database and racially equivalent Hispanic groups.
The study categorized genes with the most significant PD risk into five categories. The first group contained known PD risk-associated genes. The second category contained genes involved in lysosomal function.
The third category contained genes with known protein-protein interactions. The fourth group chose genes with the highest expression in the substantia nigra. The fifth category contained genes with lysosomal function linked to PD in the literature.
The researchers used a Geographic Information Systems (GIS)-based model and Pesticide Use Report (PUR) data to predict long-term ambient pesticide exposure to individual active components near agricultural pesticide applications.
They used the third version of the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS-III) to assess PD progression.
Results
Gene enrichment analysis revealed 36 variations in 26 genes in PD patients, with 12 detected genes including multiple enriched variants and a single enriched variant present in several individuals.
The bulk of enriched variations (26/36, 72%) were discovered in genes involved in lysosomal function, notably autophagy, and were functionally detrimental (31/36, 86%).
The bulk of the selected 36 enriched genetic variants were associated with lysosomal functions, with only a few representing the second group (four variations, 11%) or the fifth group, lysosomal function-related genes previously linked to PD development risk (three variations, 8.0%).
Instead, the bulk of variations represented the third (10 variations, 28%) and fourth group (nine variants, 25%) genes, which are distinguished by inter-protein communications with PD-related genes or elevated expressions in substantia nigral cells, respectively.
Ten genes (38%) have multiple variations, with F-box only protein 7 (FBXO7) and cyclin G-associated kinase (GAK) variants being more common in Hispanic and European subpopulations. The other 16 genes showed one variation each.
Variations in five genes (19%) were found in numerous people, whereas three genes (12%) contained multiple variations and many individuals with similar variants.
E1A-associated protein p300 (EP300) variants had the top two highest total scores, while two huntingtin genes (HTT) and FBXO7 genetic variations were also in the top ten genes with numerous variations. Huntington interacting protein-1 related (HIP1R) and Microtubule Associated Protein Tau (MAPT) showed two versions in the top twenty with the highest scores.
Acid phosphatase 2 (ACP2), Cathepsin D (CTSD), Histone deacetylase 6 (HDAC6), and Parkin RBR E3 Ubiquitin Protein Ligase (PRKN) showed only one variation in the ten highest scores.
Among 36 prioritized exonic variants, 31 (86%) were very detrimental, with Combined Annotation-Dependent Depletion (CADD) scores of 10 to 20 (11 variations, 31%) or above 20 (20 variations, 56%).
The EP300 gene had one variation scoring over 20, resulting in the highest values basis the estimated illness severity multiplied by pesticide exposure scorings.
Conclusion
The study found a relationship between lysosomal function genes and pesticide exposure in PD. The study, which examined the genetics of 757 patients, discovered that 72% of the detected variations were in genes involved in lysosomal function.
Twelve genes that had multiple variations or were present in several individuals substantiated the relationship between pesticide exposure and PD development.
The impact of these polymorphisms on function is presumably significant since 31 variants (31/36, 86%) classified as detrimental showed CADD scores ranging from 10 to 20 or very deleterious with values above 20.
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