Assessment of Mitochondrial Gene Activity in Dopaminergic Neuron Cultures Derived from Induced Pluripotent Stem Cells Obtained from Parkinson's Disease Patients

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Abstract

Introduction. Induced pluripotent stem cells (iPSCs) culturing allows modelling of neurodegenerative diseases in vitro and discovering its early biomarkers.

Our objective was to evaluate the activity of genes involved in mitochondrial dynamics and functions in genetic forms of Parkinson's disease (PD) using cultures of dopaminergic neurons derived from iPSCs.

Materials and methods. Dopaminergic neuron cultures were derived by reprogramming of the cells obtained from PD patients with SNCA and LRRK2 gene mutations, as well as from a healthy donor for control. Expression levels of 112 genes regulating mitochondrial structure, dynamics, and functions were assessed by multiplex gene expression profiling using NanoString nCounter custom mitochondrial gene expression panel.

Results. When comparing the characteristics of the neurons from patients with genetic forms of PD to those of the control, we observed variations in the gene activity associated with the mitochondrial respiratory chain, the tricarboxylic acid cycle enzyme activities, biosynthesis of amino acids, oxidation of fatty acids, steroid metabolism, calcium homeostasis, and free radical quenching. Several genes in the cell cultures with SNCA and LRRK2 gene mutations exhibited differential expression. Moreover, these genes regulate mitophagy, mitochondrial DNA synthesis, redox reactions, cellular detoxification, apoptosis, as well as metabolism of proteins and nucleotides.

Conclusions. The changes in gene network expression found in this pilot study confirm the role of disrupted mitochondrial homeostasis in the molecular pathogenesis of PD. These findings may contribute to the development of biomarkers and to the search for new therapeutic targets for the treatment of SNCA- and LRRK2-associated forms of the disease.

About the authors

Anna S. Vetchinova

Research Center of Neurology

Author for correspondence.
Email: annvet@mail.ru
ORCID iD: 0000-0003-3367-5373

Cand. Sci. (Biol.), Senior Researcher, Laboratory of Neurobiology and Tissue Engineering, Department of Molecular and Cellular Mechanisms of Neuroplasticity, Brain Science Institute

Russian Federation, Moscow

Marina R. Kapkaeva

Research Center of Neurology

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0000-0002-2833-2897

Researcher, Laboratory of Neurobiology and Tissue Engineering, Department of Molecular and Cellular Mechanisms of Neuroplasticity, Brain Science Institute

Russian Federation, Moscow

Natalia M. Mudzhiri

Research Center of Neurology

Email: Mudzhirinm@gmail.com
ORCID iD: 0000-0002-3835-6622

Junior Researcher, Laboratory of Neuromorphology, Brain Science Institute

Russian Federation, Moscow

Sergey N. Illarioshkin

Research Center of Neurology

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0000-0002-2704-6282

D. Sci. (Med.), Prof., RAS Full Member, Deputy Director for Science; Director, Brain Science Institute

Russian Federation, Moscow

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2. Decreased expression of some genes associated with mitochondrial dynamics and functions in neurons derived from patients with genetic form of PD.

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Copyright (c) 2023 Vetchinova A.S., Kapkaeva M.R., Mudzhiri N.M., Illarioshkin S.N.

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