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Brain Mitochondrial Subproteome of Rpn10-Binding Proteins and Its Changes Induced by the Neurotoxin MPTP and the Neuroprotector Isatin

A. E. Medvedev1*, O. A. Buneeva1, A. T. Kopylov1, O. V. Tikhonova1, M. V. Medvedeva2, L. N. Nerobkova3, I. G. Kapitsa3, and V. G. Zgoda1

1Institute of Biomedical Chemistry, 119121 Moscow, Russia; E-mail: professor57@yandex.ru

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

3Zakusov Institute of Pharmacology, 125315 Moscow, Russia

* To whom correspondence should be addressed.

Received September 27, 2016; Revision received October 21, 2016
Mitochondria play an important role in molecular mechanisms of neuroplasticity, adaptive changes of the brain that occur in the structure and function of its cells in response to altered physiological conditions or development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson’s disease in various experimental animal models, and also neuroprotectors. Good evidence exists in the literature that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria), and neuroprotective effects of certain antiparkinsonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS. The 19S proteasomal Rpn10 subunit is considered as a ubiquitin receptor responsible for delivery of ubiquitinated proteins to the proteasome proteolytic machinery. In this study, we investigated proteomic profiles of mouse brain mitochondrial Rpn10-binding proteins, brain monoamine oxidase B (MAO B) activity, and their changes induced by a single-dose administration of the neurotoxin MPTP and the neuroprotector isatin. Administration of isatin to mice prevented MPTP-induced inactivation of MAO B and influenced the profile of brain mitochondrial Rpn10-binding proteins, in which two pools of proteins were clearly recognized. The constitutive pool was insensitive to neurotoxic/neuroprotective treatments, while the variable pool was specifically influenced by MPTP and the neuroprotector isatin. Taking into consideration that the neuroprotective dose of isatin used in this study can result in brain isatin concentrations that are proapoptotic for cells in vitro, the altered repertoire of mitochondrial Rpn10-binding proteins may thus represent a part of a switch mechanism from targeted elimination of individual (damaged) proteins to more efficient (“global”) elimination of damaged organelles and whole damaged cells.
KEY WORDS: neuroplasticity, MPTP-induced parkinsonism, neuroprotection, isatin, Rpn10-binding proteins, brain mitochondrial fraction, subproteome

DOI: 10.1134/S0006297917030117