Lysosomal Function in Parkinson’s Disease Risk

Context

Parkinson’s disease (PD) is a complex illness with both environmental and genetic components. The pathophysiology of Parkinson’s disease depends on abnormal protein homeostasis requiring altered autophagy.

Recent studies have demonstrated the significance of autophagic function in the etiology of Parkinson’s disease (PD), with mutations in the glucosylceramidase beta (GBA1) gene elevating the risk of PD development.

Concerning the study

In this work, the genetic contributions to the risk of Parkinson’s disease (PD) in the context of long-term pesticide exposure were examined.

Researchers looked into exonic differences in lysosomal function-related genes and their potential impact on PD patients. 757 Parkinson’s, Environment, and Genes (PEG) research participants—mostly of white European or non-Hispanic descent—were screened using a special amplicon panel.

In the presence of pesticides frequently used to treat cotton, they carried out a gene-environment analysis to look at rare variants in 85 genes connected to lysosomal function and the risk of Parkinson’s disease.

By connecting known variations to their corresponding self-identified populations, the team used the Genome Aggregation Database (gnomAD) to assess variant enrichment. They prioritized enriched exonic variants based on cotton pesticide exposures and the severity of illness development in 386 individuals.

They examined variation frequencies with the majority of White European and non-Hispanic populations that are racially comparable, as well as with racially comparable Hispanic groups, in the gnomAD database.

The study divided the genes with the highest relative risk of Parkinson’s disease into five groups. There were known PD risk-associated genes in the first group. Lysosomal function-related genes were found in the second group.

Genes with documented protein-protein interactions were found in the third group. Genes having the highest expression in the substantia nigra were selected by the fourth group. Genes with lysosomal function associated with Parkinson’s disease (PD) were found in the fifth category.

The researchers predicted long-term ambient pesticide exposure to specific active components near agricultural pesticide applications using a Geographic Information Systems (GIS)-based model and Pesticide Use Report (PUR) data.

To gauge the course of Parkinson’s disease, they employed the third iteration of the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS-III).

Outcomes

In PD patients, gene enrichment analysis identified 36 variations in 26 genes; 12 of these genes had multiple enriched variants, and one gene had an enriched variant that was present in several people.

The majority of enriched variants (26/36, 72%) were found to be functionally deleterious (31/36, 86%) and to be in genes involved in lysosomal function, particularly autophagy.

Only a small number of the 36 enriched genetic variants that were chosen were linked to lysosomal functions; these four variations (11%) and the three variations (8%) that represented the fifth set of lysosomal function-related genes that had previously been linked to the risk of Parkinson’s disease development.

Instead, the majority of variations were found in the third (10 variations, 28%) and fourth groups (nine variants, 25%) of genes, which are identified by increased expressions in substantia nigral cells or by inter-protein communications with PD-related genes, respectively.

A total of ten genes (38%) exhibit multiple variations; variants of cyclin G-associated kinase (GAK) and F-box only protein 7 (FBXO7) are more prevalent in European and Hispanic subpopulations. Each of the other 16 genes displayed a single change.

Five genes (19%) showed variations that were present in a large number of individuals, while three genes (12%) showed several variations and a large number of individuals with similar variants.

The two genes with the highest total scores were E1A-associated protein p300 (EP300) variants, while the top 10 genes with the most changes also included two huntingtin genes (HTT) and FBXO7 genetic variants. Two variants of Huntington interacting protein-1 related (HIP1R) and Microtubule Associated Protein Tau (MAPT) were found in the top twenty with the highest scores.

In the ten highest scores, only one alteration was seen in Acid phosphatase 2 (ACP2), Cathepsin D (CTSD), Histone deacetylase 6 (HDAC6), and Parkin RBR E3 Ubiquitin Protein Ligase (PRKN).

Out of the 36 exonic variants that were prioritized, 31 (86%) had Combined Annotation-Dependent Depletion (CADD) values of 10 to 20 (11 variations, 31%) or above 20 (20 variations, 56%), indicating that they were highly deleterious.

With one mutation in the EP300 gene scoring higher than 20, the maximum values were obtained by multiplying the expected illness severity by the pesticide exposure scores.

In summary

The study discovered a connection between pesticide exposure and lysosomal function genes in Parkinson’s disease. 72% of the changes found in the 757 patients whose genetics were studied belonged to genes involved in lysosomal function.

The link between pesticide exposure and Parkinson’s disease development was confirmed by twelve genes that were found in numerous individuals or had various variants.

Given that 31 variations (31/36, 86%) classed as detrimental showed CADD scores ranging from 10 to 20 or very deleterious with values above 20, the impact of these polymorphisms on function is likely significant.

For more information: Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use, npj Parkinson’s disease, https://doi.org/10.1038/s41531-024-00703-4