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Alpha-synuclein aggregation, Ubiquitin proteasome system impairment, and l-Dopa response in zinc-induced Parkinsonism: resemblance to sporadic Parkinson’s disease

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Abstract

Alpha-synuclein (α-synuclein) aggregation and impairment of the Ubiquitin proteasome system (UPS) are implicated in Parkinson’s disease (PD) pathogenesis. While zinc (Zn) induces dopaminergic neurodegeneration resulting in PD phenotype, its effect on protein aggregation and UPS has not yet been deciphered. The current study investigated the role of α-synuclein aggregation and UPS in Zn-induced Parkinsonism. Additionally, levodopa (l-Dopa) response was assessed in Zn-induced Parkinsonian model to establish its closeness with idiopathic PD. Male Wistar rats were treated with zinc sulfate (Zn; 20 mg/kg; i.p.) twice weekly for 12 weeks along with respective controls. In few subsets, animals were subsequently treated with l-Dopa for 21 consecutive days following Zn exposure. A significant increase in total and free Zn content was observed in the substantia nigra of the brain of exposed groups. Zn treatment caused neurobehavioral anomalies, striatal dopamine decline, and dopaminergic neuronal cell loss accompanied with a marked increase in α-synuclein expression/aggregation and Ubiquitin-conjugated protein levels in the exposed groups. Zn exposure substantially reduced UPS-associated trypsin-like, chymotrypsin-like, and caspase-like activities along with the expression of SUG1 and β-5 subunits of UPS in the nigrostriatal tissues of exposed groups. l-Dopa treatment rescued from Zn-induced neurobehavioral deficits and restored dopamine levels towards normalcy; however, Zn-induced dopaminergic neuronal loss, reduction in tyrosine hydroxylase expression, and increase in oxidative stress were unaffected. The results suggest that Zn caused UPS impairment, resulting in α-synuclein aggregation subsequently leading to dopaminergic neurodegeneration, and that Zn-induced Parkinsonism exhibited positive l-Dopa response similar to sporadic PD.

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Acknowledgements

The authors sincerely thank the Department of Biotechnology (DBT), New Delhi, India; the Department of Science and Technology (DST), New Delhi, India, and University Grants Commission (UGC), New Delhi, India for providing research fellowship to Vinod Kumar, Namrata Mittra, and Brajesh Kumar Singh/Deepali Singh, respectively. The financial aid provided to Chetna Singh through CSIR-network program “Neurodegenerative Diseases: Causes and Corrections” (miND; BSC0115) is sincerely acknowledged. The CSIR-IITR communication number of this article is 3499.

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Authors and Affiliations

  1. Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India

    Vinod Kumar, Deepali Singh, Brajesh Kumar Singh, Shweta Singh, Namrata Mittra & Chetna Singh

  2. Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226 001, Uttar Pradesh, India

    Vinod Kumar, Deepali Singh, Namrata Mittra & Chetna Singh

  3. Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India

    Rakesh Roshan Jha & Devendra Kumar Patel

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  1. Vinod Kumar
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Correspondence to Chetna Singh.

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This study was approved by the Institutional Animal Ethics Committee. The experiments were performed as per the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) throughout the study.

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CSIR-IITR Communication Number: 3499

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Kumar, V., Singh, D., Singh, B.K. et al. Alpha-synuclein aggregation, Ubiquitin proteasome system impairment, and l-Dopa response in zinc-induced Parkinsonism: resemblance to sporadic Parkinson’s disease. Mol Cell Biochem 444, 149–160 (2018). https://doi.org/10.1007/s11010-017-3239-y

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