Inhibition by pesticides of the DJ-1/Park7 protein related to Parkinson disease.

Mathas, Nicolas; Poncet, Gabrielle; LAURENT, Catherine; LARIGOT, Lucie; LE-GRAND, Béatrice; GONIS, Elodie; Birman, Serge; Galardon, Erwan; SARI, Marie-Agnès; TIOUAINI, Mounira; NIOCHE, Pierre; Barouki, Robert; COUMOUL, Xavier; Mansuy, Daniel; Dairou, Julien

doi:10.1016/j.tox.2023.153467

Cited by 5 publications

(5 citation statements)

References 46 publications

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“… 49 Further, six of the top 10 SNPs prioritized for Parkinson disease are located in the PARK7 gene, which is implicated in early onset Parkinson disease when defects are present in the gene. 50 Evidence also suggests PARK7 protective activity can be inhibited by thiocarbamates like thiram, 51 and thiram was a priority pesticide for Parkinson disease in our analysis. Additionally, many of the SNPs/genes we found with literature supporting their role in pesticide-induced nervous system disease (Table S1, e.g., rs1130409 in APEX 40 ) were identified as high-priority SNPs/genes in our analysis.…”

Section: Discussionmentioning

confidence: 67%

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Kosnik,

Antczak,

Fantke

2024

Environ Health Perspect

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Background: Genetic susceptibility to chemicals is incompletely characterized. However, nervous system disease development following pesticide exposure can vary in a population, implying some individuals may have higher genetic susceptibility to pesticide-induced nervous system disease. Objectives: We aimed to build a computational approach to characterize single-nucleotide polymorphisms (SNPs) implicated in chemically induced adverse outcomes and used this framework to assess the link between differential population susceptibility to pesticides and human nervous system disease. Methods: We integrated publicly available datasets of Chemical–Gene, Gene–Pathway, and SNP–Disease associations to build Chemical–Pathway–Gene–SNP–Disease linkages for humans. As a case study, we integrated these linkages with spatialized pesticide application data for the US from 1992 to 2018 and spatialized nervous system disease rates for 2018. Through this, we characterized SNPs that may be important in states with high disease occurrence based on the pesticides used there. Results: We found that the number of SNP hits per pesticide in US states positively correlated with disease incidence and prevalence for Alzheimer’s disease, Parkinson disease, and multiple sclerosis. We performed frequent itemset mining to differentiate pesticides used over time in states with high and low disease occurrence and found that only 19% of pesticide sets overlapped between 10 states with high disease occurrence and 10 states with low disease occurrence rates, and more SNPs were implicated in pathways in high disease occurrence states. Through a cross-validation of subsets of five high and low disease occurrence states, we characterized SNPs, genes, pathways, and pesticides more frequently implicated in high disease occurrence states. Discussion: Our findings support that pesticides contribute to nervous system disease, and we developed priority lists of SNPs, pesticides, and pathways for further study. This data-driven approach can be adapted to other chemicals, diseases, and locations to characterize differential population susceptibility to chemical exposures. https://doi.org/10.1289/EHP14108

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Section: Discussionmentioning

confidence: 67%

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Kosnik,

Antczak,

Fantke

2024

Environ Health Perspect

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“…, DJ-1 gene) play an important causative role in mitochondrial dysfunction, protein misfolding, and oxidative stress (OS). In line with this, Mathas and co-workers have recently shown that PQ 2+ and MB inhibited the esterase activity of DJ-1, a critical cellular antioxidant and signaling protein, − by 20 ± 4 and 100 ± 6%, respectively. Unfortunately, the esterase activity of DJ-1 has no identified physiological role.…”

Section: Introductionmentioning

confidence: 53%

“…Despite this drawback, the same researchers showed that either H 2 O 2 , a subproduct of PQ 2+ redox reaction, 13 or MB fully oxidized DJ-1 protein. 12 This observation suggests that this interaction could be one of the various biological effects of these pesticides that may explain their involvement in the development of sporadic PD. Therefore, one of the main challenges is to identify synthetic and/or natural molecules that might protect DJ-1 against pesticide blockage, thereby leading to restoration of its original function.…”

Section: ■ Introductionmentioning

confidence: 98%

“…Unfortunately, the esterase activity of DJ-1 has no identified physiological role. Despite this drawback, the same researchers showed that either H 2 O 2 , a subproduct of PQ 2+ redox reaction, or MB fully oxidized DJ-1 protein . This observation suggests that this interaction could be one of the various biological effects of these pesticides that may explain their involvement in the development of sporadic PD.…”

Section: Introductionmentioning

confidence: 99%

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Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS¹⁰⁶ and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson’s Disease

Mendivil-Perez,

Felizardo-Otalvaro,

Jimenez-Del-Rio

et al. 2023

ACS Chem. Neurosci.

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Parkinson's disease (PD), a progressive neurodegenerative movement disorder, has reached pandemic status worldwide. This neurologic disorder is caused primarily by the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Unfortunately, there are no therapeutic agents that slow or delay the disease progression. Herein, menstrual stromal cell-derived dopamine-like neurons (DALNs) intoxicated with paraquat (PQ 2+ )/maneb (MB) were used as a model system to elucidate the mechanism by which CBD protects the neural cell from apoptosis in vitro. According to immunofluorescence microscopy, flow cytometry, cell-free assay, and molecular docking analysis, we demonstrate that CBD offers protection to DALNs against PQ 2+ (1 mM)/ MB (50 μM)-induced oxidative stress (OS) by simultaneously (i) decreasing reactive oxygen species (ROS: O 2•− , H 2 O 2 ), (ii) maintaining the mitochondrial membrane potential (ΔΨ m ), (iii) directly binding to stress sensor protein DJ-1, thereby blunting its oxidation from DJ-1CYS 106 -SH into DJ-1CYS 106 -SO 3 , and (iv) directly binding to pro-apoptotic protease protein caspase 3 (CASP3), thereby disengaging neuronal dismantling. Furthermore, the protective effect of CBD on DJ-1 and CASP3 was independent of CB1 and CB2 receptor signaling. CBD also re-established the Ca 2+ influx in DALNs as a response to dopamine (DA) stimuli under PQ 2+ /MB exposure. Because of its powerful antioxidant and antiapoptotic effects, CBD offers potential therapeutic utility in the treatment of PD.

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“…ROS are chemical reactive species containing oxygen (e.g., peroxides, hydroxyl radicals and superoxides) induced by UV radiation, tobacco smoke, drugs, xenobiotics and pesticides, the latter two being of high relevance for the development of PD [ 73 ]. Notably, a recent study investigating the possible inhibitory effects of one hundred pesticides on DJ-1 uncovered that 15 of them were effective inhibitors of the human DJ-1 protein [ 74 ]. All of them were previously linked to PD, such as paraquat, which causes oxidative stress, DA neuronal loss and PD symptoms (Table 1 ) [ 75 , 76 ].…”

Section: Roles Of Park7/dj-1 and Its Involvement In Parkinson’s Diseasementioning

confidence: 99%

PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target

Mogensen

Scafidi

Poli

et al. 2023

J Neuroinflammation

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Microglia are the immune effector cells of the brain playing critical roles in immune surveillance and neuroprotection in healthy conditions, while they can sustain neuroinflammatory and neurotoxic processes in neurodegenerative diseases, including Parkinson’s disease (PD). Although the precise triggers of PD remain obscure, causative genetic mutations, which aid in the identification of molecular pathways underlying the pathogenesis of idiopathic forms, represent 10% of the patients. Among the inherited forms, loss of function of PARK7, which encodes the protein DJ-1, results in autosomal recessive early-onset PD. Yet, although protection against oxidative stress is the most prominent task ascribed to DJ-1, the underlying mechanisms linking DJ-1 deficiency to the onset of PD are a current matter of investigation. This review provides an overview of the role of DJ-1 in neuroinflammation, with a special focus on its functions in microglia genetic programs and immunological traits. Furthermore, it discusses the relevance of targeting dysregulated pathways in microglia under DJ-1 deficiency and their importance as therapeutic targets in PD. Lastly, it addresses the prospect to consider DJ-1, detected in its oxidized form in idiopathic PD, as a biomarker and to take into account DJ-1-enhancing compounds as therapeutics dampening oxidative stress and neuroinflammation.

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Inhibition by pesticides of the DJ-1/Park7 protein related to Parkinson disease.

Cited by 5 publications

References 46 publications

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS¹⁰⁶ and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson’s Disease

PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target

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Inhibition by pesticides of the DJ-1/Park7 protein related to Parkinson disease.

Cited by 5 publications

References 46 publications

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS106 and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson’s Disease

PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target

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Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS¹⁰⁶ and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson’s Disease