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Eleven Crucial Pesticides Appear to Regulate Key Genes That Link MPTP Mechanism to Cause Parkinson's Disease through the Selective Degeneration of Dopamine Neurons.

ABSTRACT: Pesticides kill neurons, but the mechanism leading to selective dopaminergic loss in Parkinson's disease (PD) is unknown. Understanding the pesticide's effect on dopaminergic neurons (DA) can help to screen and treat PD. The critical uptake of pesticides by the membrane receptors at DA is hypothesized to activate a signaling cascade and accelerate degeneration. Using MPTP as a reference, we demonstrate the mechanisms of eleven crucial pesticides through molecular docking, protein networks, regulatory pathways, and prioritization of key pesticide-regulating proteins. Participants were recruited and grouped into control and PD based on clinical characteristics as well as pesticide traces in their blood plasma. Then, qPCR was used to measure pesticide-associated gene expression in peripheral blood mononuclear cells between groups. As a result of molecular docking, all eleven pesticides and the MPTP showed high binding efficiency against 274 membrane receptor proteins of DA. Further, the protein interaction networks showed activation of multiple signaling cascades through these receptors. Subsequent analysis revealed 31 biological pathways shared by all 11pesticides and MPTP that were overrepresented by 46 crucial proteins. Among these, CTNNB1, NDUFS6, and CAV1 were prioritized to show a significant change in gene expression in pesticide-exposed PD which guides toward therapy.

SUBMITTER: Anirudhan A

PROVIDER: S-EPMC10377611 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Eleven Crucial Pesticides Appear to Regulate Key Genes That Link MPTP Mechanism to Cause Parkinson's Disease through the Selective Degeneration of Dopamine Neurons.

Anirudhan Athira A Mattethra George Chandy GC Alzahrani Khalid J KJ Banjer Hamsa Jameel HJ Alzahrani Fuad M FM Halawani Ibrahim F IF Patil Shankargouda S Sharma Ashutosh A Paramasivam Prabu P Ahmed Shiek S S J SSSJ

Brain sciences 20230628 7

Pesticides kill neurons, but the mechanism leading to selective dopaminergic loss in Parkinson's disease (PD) is unknown. Understanding the pesticide's effect on dopaminergic neurons (DA) can help to screen and treat PD. The critical uptake of pesticides by the membrane receptors at DA is hypothesized to activate a signaling cascade and accelerate degeneration. Using MPTP as a reference, we demonstrate the mechanisms of eleven crucial pesticides through molecular docking, protein networks, regul ...[more]

PMID: 37508933

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Project description:Asymmetric dopaminergic degeneration of the striatum is a characteristic feature of Parkinson's disease, associated with right-left asymmetry in motor function. As such, studying asymmetry provides insights into progressive neurodegeneration between cerebral hemispheres. Given the impact of Lewy pathology on various neurotransmitter systems beyond the dopaminergic, it may be that other neuronal systems in the predominantly affected hemisphere are similarly affected. According to this hypothesis, asymmetry in dopaminergic degeneration would be expected to coincide with asymmetry in other neurotransmitter systems. Consequently, asymmetry in functions primarily dependent on dopaminergic integrity, such as motor function, should correlate with asymmetry in bilateral non-motor functions that rely on other cerebral systems, such as pupillary function. Therefore, this study tested whether right-left asymmetry in bilateral non-motor measures correlates with asymmetry in dopaminergic striatal integrity. We also tested whether asymmetric striatal degeneration is associated with greater asymmetry in non-motor measures overall. Using a comparative cross-sectional design, we recruited newly diagnosed patients with Parkinson's disease with predominantly right-sided (n = 18), left-sided (n = 15) or symmetric nigrostriatal denervation (n = 15) assessed on dopamine PET. Detailed examinations of lateralized non-motor function included lacrimation, hand skin wrinkling, salivation, olfaction and pupillary function. Healthy controls were recruited for comparison. We observed a moderate-to-strong correlation between right-left asymmetry of putamen dopamine binding and asymmetry in pupillary redilation speed [Spearman's rank correlation coefficient (rs ) = -0.53, 95% confidence interval (-0.77; -0.14), P = 0.0084]. We also observed moderate correlations between non-negative putaminal asymmetry and lacrimation [rs = 0.35, (-0.00; 0.62), P = 0.0464] and word recognition [rs = 0.36, (0.01; 0.63), P = 0.0410]. However, none were significant after false discovery rate correction. We observed significant group differences in non-negative asymmetry in salivation (P = 0.0390, ANOVA) and a trend towards greater asymmetric lacrimation in participants with asymmetric striatal dopamine loss compared with healthy controls (P = 0.0330, unadjusted). Additionally, participants with asymmetric striatal dopaminergic binding showed greater, though non-significant, asymmetry in all pupillary measures compared with those with symmetric dopaminergic binding. In conclusion, this study contributes to our understanding of neurodegeneration progression in Parkinson's disease and suggests a link between dopaminergic degeneration and non-motor measures related to autonomic function, particularly salivation, lacrimation and pupillary function. While our findings do not support a strict right-left hemispheric association between non-motor functions and dopaminergic degeneration, potential relationships may exist between these features and asymmetrical degeneration in other neuronal systems, such as the cholinergic.

Dataset Information

Eleven Crucial Pesticides Appear to Regulate Key Genes That Link MPTP Mechanism to Cause Parkinson's Disease through the Selective Degeneration of Dopamine Neurons.

Publications

Eleven Crucial Pesticides Appear to Regulate Key Genes That Link MPTP Mechanism to Cause Parkinson's Disease through the Selective Degeneration of Dopamine Neurons.

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