Abstract
Owing to its lipophilic nature, cypermethrin makes entry into the brain through the blood–brain barrier and causes severe damage to the nigrostriatal dopaminergic neurons after prolonged exposure. Following substantial accrual in the brain, cypermethrin induces the abnormal expression and accumulation of α-synuclein. Besides, cytochrome P450 2E1 (CYP2E1) causes free radical generation leading to lipid peroxidation in toxicant-induced parkinsonism. Conversely, 4-hydroxynonenal (4-HNE), a byproduct of lipid peroxidation, is known to contribute to neuronal damage. The current investigation aimed to explicate the participation of endogenous redox-sensitive proteins in cypermethrin-induced cellular and animal models of parkinsonism. The qualitative and quantitative expressions of selected redox-sensitive proteins were evaluated employing the standard procedures. Cypermethrin reduced the expression of peroxiredoxin 3 (Prx3), thioredoxin 2 (Trx2), and protein deglycase-1 (DJ-1). Knocking down of Prx3, Trx2, or DJ-1 further reduced the level of expression in the cypermethrin-treated group. Reduction in the expression of Prx3, Trx2, or DJ-1 was found to be associated with overexpression of α-synuclein and 4-HNE modification of proteins. Besides, cypermethrin increased the expression of CYP2E1, which was not altered after Prx3 or Trx2 knockdown. However, knocking down the DJ-1 augmented the level of CYP2E1 both in the cypermethrin-treated group and its respective control. The outcomes of the study demonstrate that cypermethrin reduces the level of Prx3, Trx2, and DJ-1 proteins. While the reduction in the expression of selected redox-sensitive proteins leads to α-synuclein overexpression and 4-HNE modification of proteins, DJ-1 attenuation is also linked with increased CYP2E1 expression, which in turn could lead to oxidative stress-mediated neuronal damage.
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The data are deposited to the institutional repository. The same may be possible to obtain from the corresponding author upon reasonable request.
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Acknowledgements
Charul Rajput appreciates the Council of Scientific and Industrial Research (CSIR), India, for bestowing her fellowship for research. The generousness of the Department of Biotechnology, India, is also recognized for offering monetary support to the investigation as well as for providing research fellowship to Alika Sarkar. The CSIR-IITR communication number of this article is 3746.
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The research was funded by the Department of Biotechnology, India.
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Charul Rajput and Alika Sarkar generated, captured, and evaluated the experimental data as well as drawn and arranged the figures and images of the manuscript. The initial draft of the manuscript was also made available by the first two authors. Mahendra Pratap Singh hypothesized the experimental design and lengthily revised the text of the first version of the paper. All investigators endorsed the final description of the manuscript.
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Charul Rajput and Alika Sarkar Contributed equally to this work
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Rajput, C., Sarkar, A. & Singh, M.P. Involvement of Peroxiredoxin-3, Thioredoxin-2, and Protein Deglycase-1 in Cypermethrin-Induced Parkinsonism . Mol Neurobiol 58, 4745–4757 (2021). https://doi.org/10.1007/s12035-021-02456-0
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DOI: https://doi.org/10.1007/s12035-021-02456-0