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. 2021 Jan;67(1):51-65.
doi: 10.18097/PBMC20216701051.

[Changes in the mitochondrial subproteome of mouse brain Rpn13-binding proteins induced by the neurotoxin MPTP and the neuroprotector isatin]

[Article in Russian]
O A Buneeva  1 , A T Kopylov  1 , O V Gnedenko  1 , M V Medvedeva  2 , I G Kapitsa  3 , E A Ivanova  3 , A S Ivanov  1 , A E Medvedev  1
Affiliations

[Changes in the mitochondrial subproteome of mouse brain Rpn13-binding proteins induced by the neurotoxin MPTP and the neuroprotector isatin]

[Article in Russian]
O A Buneeva et al. Biomed Khim. 2021 Jan.

Abstract
in English, Russian

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 play 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. (2020) Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 14, 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 differentiation. Selected biosensor validation confirmed the interaction of Rpn13 subunit of proteasome with some proteins (glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, histones H2A and H2B) revealed while proteomic profiling. The results obtained testify 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.

Mitokhondrial'naia disfunktsiia i sboĭ v rabote ubikvitin-proteasomnoĭ sistemy (UPS) vnosiat sushchestvennyĭ vklad v razvitie bolezni Parkinsona (BP). Sub"edinitsa proteasomy Rpn13, raspolozhennaia na reguliatornoĭ subchastitse (19S), igraet vazhnuiu rol' v dostavke belkov, podlezhashchikh degradatsii, v proteoliticheskuiu chast' (20S) proteasomy. Ranee nami obnaruzhen riad mitokhondrial'nykh belkov mozga, spetsificheski sviazyvaiushchikhsia s Rpn13 (Buneeva i dr., Biomeditsinskaia khimiia, 2020, 66(2), 138-144). V dannoĭ rabote izucheno vliianie neĭrotoksina 1-metil-4-fenil-1,2,3,6-tetragidropiridina (MFTP) i neĭroprotektora izatina na mitokhondrial'nyĭ subproteom Rpn13-sviazyvaiushchikh belkov mozga myshi. Vvedenie MFTP (30 mg/kg) zhivotnym vyzyvalo razvitie dvigatel'nykh narusheniĭ, svoĭstvennykh dlia BP, a predvaritel'noe vvedenie izatina (100 mg/kg) oslablialo ikh vyrazhennost'. Pri étom vvedenie MFTP, izatina ili ikh kombinatsii (izatin + MFTP) privodilo k izmeneniiu obshchego chisla i sostava Rpn13-sviazyvaiushchikh belkov. Vvedenie MFTP snizhalo obshchee chislo Rpn13-sviazyvaiushchikh belkov po sravneniiu s kontrolem, a vvedenie izatina pered vvedeniem MFTP ili bez MFTP privodilo k sushchestvennomu uvelicheniiu chisla Rpn13-sviazyvaiushchikh belkov preimushchestvenno iz funktsional'noĭ gruppy belkov, uchastvuiushchikh v reguliatsii metabolizma belkov, a takzhe ékspressii genov, kletochnogo deleniia i differentsirovki. Vyborochnaia biosensornaia validatsiia podtverdila vzaimodeĭstvie riada belkov (glitseral'degid-3-fosfatdegidrogenaza, piruvatkinaza, gistony N2A i N2V), vyiavlennykh v khode proteomnogo profilirovaniia, s sub"edinitseĭ proteasomy Rpn13. Poluchennye rezul'taty svidetel'stvuiut o tom, chto v usloviiakh éksperimental'nogo MFTP-indutsirovannogo parkinsonizma neĭroprotektornoe deĭstvie izatina mozhet byt' napravleno na vzaimodeĭstvie mitokhondriĭ s komponentami UPS.

Keywords: MPTP-induced parkinsonism; Rpn13-binding proteins; isatin; mitochondrial fraction of the brain; neuroprotector; subproteome.

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