Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use

Abstract

Parkinson’s disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson’s, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized 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. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.

Neuroprotective Potentials of Berberine in Rotenone-Induced Parkinson’s Disease-like Motor Symptoms in Rats

“…Rotenone (RTN) (≥95%; Sigma, St. Louis, MO, USA), with the chemical name ((2R,6aS,12aS)-1,2,6,6a,12,12a-hexahydro-2-isopropenyl-8,9-dimethoxychromeno [3,4-b]furo [2,3-h]chromen-6-one), was prepared in a 1% DMSO solution and administered subcutaneously (s.c.). Berberine (BBR) (≥95%; Sigma, St. Louis, MO, USA), with the chemical name (9,10-Dimethoxy-7,8,13,13a-tetradehydro-2 ′ H- [1,3]dioxolo[4 ′ ,5 ′ :2,3]berbin-7-ium), was dissolved in double-distilled water and administered orally (p.o.). Trigonelline (TGN) (Sigma, St. Louis, MO, USA), with the chemical name (1-Methylpyridin-1-ium-3-carboxylate), was mixed in normal saline and administered intraperitoneally (i.p.).…”

“…Recent epidemiological research has linked environmental factors, including exposure to pesticides, with the onset of idiopathic Parkinson’s disease (PD) [ 1 , 2 , 3 ]. Rotenone (RTN), a hydrophobic compound derived from Leguminosae plant roots and utilized as a natural pesticide, easily penetrates the blood–brain barrier (BBB) and strongly inhibits mitochondrial complex I in the electron transport chain [ 4 ].…”

“…Rotenone (RTN), a hydrophobic compound derived from Leguminosae plant roots and utilized as a natural pesticide, easily penetrates the blood–brain barrier (BBB) and strongly inhibits mitochondrial complex I in the electron transport chain [ 4 ]. Studies have demonstrated a correlation between RTN exposure and increased PD risk in affected populations [ 1 , 2 , 3 , 4 ]. Moreover, RTN induces a spectrum of behavioral, neuropathological, and biochemical manifestations in rodents reminiscent of those observed in human PD, rendering it a valuable disease model for decades [ 4 , 5 , 6 ].…”