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Changes in the Mitochondrial Subproteome of Mouse Brain Rpn13-Binding Proteins Induced by the Neurotoxin MPTP and the Neuroprotector Isatin

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Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry Aims and scope Submit manuscript

Abstract—

Mitochondrial dysfunction and ubiquitin-proteasome system (UPS) failure contribute significantly to the development of Parkinson’s disease (PD). The proteasome subunit Rpn13 located on the regulatory (19S) subparticle plays an important role in the delivery of proteins, subjected to degradation, to the proteolytic (20S) part of proteasome. We have previously found several brain mitochondrial proteins specifically bound to Rpn13 (Buneeva et al., Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, (2020), vol. 14, pp. 297−305). In this study we have investigated the effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroprotector isatin on the mitochondrial subproteome of Rpn13-binding proteins of the mouse brain. Administration of MPTP (30 mg/kg) to animals caused movement disorders typical of PD, while pretreatment with isatin (100 mg/kg, 30 min before MPTP) reduced their severity. At the same time, the injection of MPTP, isatin, or their combination (isatin + MPTP) had a significant impact on the total number and the composition of Rpn13-binding proteins. The injection of MPTP decreased the total number of Rpn13-binding proteins in comparison with control, and the injection of isatin prior to MPTP or without MPTP caused an essential increase in the number of Rpn13-binding proteins, mainly of the functional group of proteins participating in the protein metabolism regulation, gene expression, and cell division and differentiation. Selected biosensor validation confirmed the interaction of the proteasome Rpn13 subunit with some proteins (glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, histones H2A and H2B) recognized during proteomic profiling. The results obtained suggest that under the conditions of experimental MPTP-induced parkinsonism the neuroprotective effect of isatin may be aimed at the interaction of mitochondria with the components of UPS.

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ACKNOWLEDGMENTS

Mass spectrometry analysis of proteins and SPR analysis of intermolecular interactions was performed using equipment and resources of the Center for Collective Use “Human Proteome” at the Institute of Biomedical Chemistry.

Funding

The work done in the framework of the Russian Federation fundamental research program for the long-term period for 2021−2030 (mass spectrometry analysis) was partially supported by the Russian Foundation for Basic Research (project no. 19-015-00073a) (the study of the locomotor activity of animals under the influence of the neurotoxin MPTP and the neuroprotector isatin and the isolation and sample preparation of Rpn-binding proteins of the brain mitochondria, biosensor analysis).

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Authors and Affiliations

  1. Institute of Biomedical Chemistry, ul. Pogodinskaya 10, 119121, Moscow, Russia

    O. A. Buneeva, A. T. Kopylov, O. V. Gnedenko, A. S. Ivanov & A. E. Medvedev

  2. Biological Faculty, Moscow State University, 119991, Moscow, Russia

    M. V. Medvedeva

  3. Zakusov Institute of Pharmacology, 125315, Moscow, Russia

    I. G. Kapitsa & E. A. Ivanova

Authors
  1. O. A. Buneeva
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  2. A. T. Kopylov
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  3. O. V. Gnedenko
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  4. M. V. Medvedeva
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  5. I. G. Kapitsa
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  6. E. A. Ivanova
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  7. A. S. Ivanov
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  8. A. E. Medvedev
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Correspondence to O. A. Buneeva.

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The authors declare that they have no conflicts of interest. The experimental modeling of Parkinson’s disease and the study of changes in the locomotor activity of mice induced by the neurotoxin MPTP and the neuroprotector isatin were carried out in compliance with the generally accepted norms of the humane care of laboratory animals.

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Translated by A. Medvedev

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Buneeva, O.A., Kopylov, A.T., Gnedenko, O.V. et al. Changes in the Mitochondrial Subproteome of Mouse Brain Rpn13-Binding Proteins Induced by the Neurotoxin MPTP and the Neuroprotector Isatin. Biochem. Moscow Suppl. Ser. B 15, 199–214 (2021). https://doi.org/10.1134/S1990750821030021

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