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Laboratory of Cell Physiology and Pathology

Invited researcher Andrey Yuriyevich Abramov
Contract number
075-15-2019-1877
Time span of the project
2019-2021

As of 15.02.2021

27
Number of staff members
15
scientific publications
2
Objects of intellectual property
General information

Name of the project: Study of the mechanisms of mitochondrial dysfunction in cell models in neurodegenerative diseases

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Project objective:

1. Determining how toxins or abnormal proteins encoded by mutated gene cause changes in mitochondrial function.

2. Developing a strategy to protect neurons in context neurodegenerative diseases based on correction of functions of mitochondria.

3. Developing an in vivo method of detecting pathological changes in mitochondrial metabolism during neurodegenerative diseases.

The practical value of the study

Scientific results obtained

The method for obtaining models of neurodegenerative diseases from iPSC patients with SNCA, PINK1, and PINK1/Parkin double mutation genes has been developed. The toxic effect of water-soluble aggregates containing a small number of monomers and abnormal proteins encoded by mutated genes on mitochondrial function has been proven. It was found that the selectivity of brain lesions in neurodegeneration can be largely due to the difference between energy formation and consumption. The physiological significance of the epinephrine-induced calcium signal for regulating brain blood vessels diameter has been shown. The methodological foundations of new strategies and methods for protecting cells from oxidative stress based on various protective compositions (with substrate, direct and indirect antioxidant effects) have been developed. It was determined that the production of singlet oxygen under 1267 nm laser irradiation causes a protective and regenerative effect on the altered mitochondrial metabolism in human iPSC-derived neurons with mutations associated with various hereditary forms, and increases cell survival.

Implementation of research results

Methods have been developed for obtaining models of neurodegenerative diseases from iPSC patients with SNCA, PINK1, and PINK1/Parkin double mutation genes, which can be used in large-scale preclinical trials of potential neuroprotective compounds. The composition including substrates of the tricarboxylic acid cycle (in particular, sodium lactate) and antioxidants (dihydroquercetin-pentanicotinate) has been developed to protect neurons from oxidative stress in mitochondrial dysfunction. It is planned to be used in the future for the development of medicinal neuroprotective compounds.

The method of correction of mitochondrial cell metabolism under the influence of 1267 nm laser radiation has been developed in order to create an original method of neuroprotective laser exposure. The effect of sodium lactate and sodium paruvate composition on the level of mitochondrial membrane potential and NADH autofluorescence in human fibroblasts has been evaluated. The results obtained in accordance with the contract for the performance of research work will be used by Arnilab LLC for the development of new means for cells protection from neurodegeneration in familial forms of Parkinson's disease.

Negotiations are underway to conduct joint research with Mitocholine Ltd.

Education and retraining of personnel

The main professional educational program of higher education (the level of highly qualified personnel training) in 06.06.01 Biological sciences (Physiology direction) has been developed. The PhD student enrolled for this direction performs research work under the supervision of the leading scientist Andrey Abramov.

The educational program of higher education in 12.04.04 Biotechnical systems and technologies (Photonics and electronics in biomedical practice direction) has been developed. 12 Masters’ students have been enrolled. A complete set of documentation has been developed (a work program, a course of lectures, guidelines for the implementation of laboratory, practical and independent works) for the discipline "Modern microscopy methods ".

At Pushchinsky Scientific Center for Biological Studies of the Russian Academy of Sciences a theoretical and practical course on fluorescence and confocal microscopy has been developed to measure the parameters of cell cultures. Internships have been organized for 13 laboratory employees.

On December 17, 2020, the employee of the laboratory Evgeniya Fedotova has defended her PhD thesis "PH-dependent regulation of mitophagy in the norm and the cellular models of Parkinson's disease" in 03.01.02 Biophysics.

In December 2020, the Sc.D. thesis of the employee of the laboratory Andrey Dunaev "Methods and means of multimodal optical diagnostics of microcirculatory-tissue systems of the human body" in 05.11.17 Devices, systems, and medical supplies has been accepted for the defense.

Infrastructure transformations

Preparations are being held to create a network laboratory at Orel State University, the purpose of which will be to organize, coordinate, and conduct scientific research, as well as scientific, information, research, and consulting support of innovations, and network interaction of scientific and educational institutions, organizations and educational systems.

International and domestic cooperation

Together with the Сenter of collective use "Genomic Editing" of Institute of Genе Biology of Russian Academy of Sciences the project "Investigation of neurodegeneration mechanisms in the hereditary form of lateral amyotrophic sclerosis" was submitted to a grant contest of the Russian Science Foundation. As part of the project, it is planned to solve the current problem of biology and medicine associated with obtaining fundamental knowledge about: the molecular and cellular mechanisms for the development of lateral amyotrophic sclerosis associated with the mutation of the FUS gene; the identification of potential markers for early diagnosis of this disease; the search for new cell protection paths in neurodegeneration.

Within the cooperation with Institute of Genе Biology of Russian Academy of Sciences, joint research on animals’ models of other pathologies is carried out, for example, in genetically modified mice carrying the mutant HPRT1 gene. This mutation is associated with Lesch-Nyhan syndrome. This pathology is associated with the accumulation of uric acid in cells and manifests in self-harm behavior.

The direction of research performed jointly with the Center of collective use of scientific equipment for the creation of genetically modified animal lines and studying the effectiveness of compounds on original cellular and transgenic models of human neurodegenerative diseases at Institute of Physiologically Active Substances of Russian Academy of Sciences is the study of mitochondrial pathology in three lines of genetically modified mice with knocked out synuclein genes (SNCA, SNCB, SNCG, two lines with a double knockout of α-, β- and α-, γ-synucleins and one line with a triple knockout of α-, β- , γ-synucleins). The studies cover a wide range of cerebral cell parameters, including generation of the reactive oxygen species, the content of endogenous antioxidants (reduced glutathione), the development of intracellular calcium signaling, the functioning of the electron transport chain of mitochondria.

At the stage of pilot experiments coordination, there is a work on the study of mitochondrial dysfunction in the development of endometrial pathologies (in particular, adenomyosis). At the moment, data is already obtained and indicates a significantly higher level of reactive oxygen species in the cells from patients with pathology, compared with the cells of conditionally healthy volunteers. A number of practicing gynecologists, as well as companies producing specialized drugs, are interested in collaboration in this area.

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Abramov A.Y., Potapova E.V., Dremin V.V., Dunaev A.V.
Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration. Life (Basel). 2020. June (10(7)).
Novikova I.N., Manole A., Zherebtsov E.A., Stavtsev D.D., Vukolova M.N., Dunaev A.V., Angelova P.R., Abramov A.Y.
Adrenaline induces calcium signal in astrocytes and vasoconstriction via activation of monoamine oxidase. Free Radical Biology and Medicine. 2020. November (159).
Cheng X., Vinokurov A.Y., Zherebtsov E.A., Stelmashchuk O.A., Angelova P.R., Esteras N., Abramov A.Y.
Variability of mitochondrial energy balance across brain regions. Journal of Neurochemistry. 2020. November.
Sokolovski S.G., Zherebtsov E.A., Kar R.K., Golonka D., Stabel R., Chichkov N.B., Gorodetsky A., Schapiro I., Möglich A., Rafailov E.U.
Two-photon conversion of a bacterial phytochrome. Biophysical Journal. 2021. February (120(5)).
Berezhnov A.V., Fedotova E.I., Sergeev A.I., Teplov I.Y., Abramov A.Y.
Dopamine controls neuronal spontaneous calcium oscillations via astrocytic signal. Cell Calcium. 2021. January (94).
Dolgikh A.I., Stelmashchuk O.A., Vinokurov A.Y., Zherebtsov E.A., Abramov A.Y.
Measurements of mitochondrial NADH pool and NADH production rate in acute brain slices and primary cell cultures using live cell imaging. Proc. SPIE 11845, Saratov Fall Meeting 2020: Optical and Nanotechnologies for Biology and Medicine. 2021. May.
Palalov A., Gorlin P., Seryogina E., Gorbunova M., Alekseev A., Zherebtsov E., Abramov A.
NADH growth rate evaluation in different rat brain regions by fluorescence spectroscopy. Proc. SPIE 11845, Saratov Fall Meeting 2020: Optical and Nanotechnologies for Biology and Medicine. 2021. May
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