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Comparative Analysis of MPTP Neurotoxicity in Mice with a Constitutive Knockout of the α-Synuclein Gene

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Abstract

Aggregated forms of α-synuclein are core components of pathohistological inclusions known as Lewy bodies in substantia nigra (SN) neurons of patients with Parkinson’s disease (PD). The role of α-synuclein in selective loss of SN dopaminergic neurons (DNs) in PD is studied in mice knocked out in the α-synuclein gene. The new mouse strain delta flox KO with a constitutive knockout of the α-synuclein gene models the end point of in vivo deletion of the α-synuclein gene in mice with a conditional knockout and has no foreign sequence in the modified genomic locus, thus differing from all other α-synuclein knockout mouse strains. The effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is used to model PD, was compared between delta flox KO mice and mice of the well-known α-synuclein knockout strain AbKO. Subchronic MPTP administration, which models early PD, was found to reduce the dopamine content and to change the ratio of dopamine metabolites in the striatum to the same levels in delta flox KO, АbKO, and wild-type mice. Overt locomotor defects were not observed after MPTP treatment, but gait testing in a CatWalk XT (Noldus) system revealed identical gait deviations in mice of the two strains and control wild-type mice. Based on the findings, a similar mechanism of neurotoxic damage to DNs was assumed for delta flox KO and AbKO mice.

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Funding

This work was supported by the Russian Science Foundation (project no. 19-14-00064). Behavioral testing was supported by the Russian Foundation for Basic Research (project no. 19-315–90049) and was carried out using equipment of the Collective Access Center at the Institute of Physiologically Active Compounds.

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  1. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Moscow oblast, Russia

    K. D. Chaprov, E. V. Teterina, A. Yu. Roman, T. A. Ivanova, E. A. Lysikova, O. A. Lytkina, I. V. Koroleva, R. K. Ovchinnikov & M. S. Kukharsky

  2. Institute of General Pathology and Pathophysiology, 125315, Moscow, Russia

    V. V. Goloborshcheva, V. G. Kucheryanu & S. G. Morozov

  3. Pirogov Russian National Research Medical University, 117997, Moscow, Russia

    N. Ia. Popova, A. I. Antohin, R. K. Ovchinnikov & M. S. Kukharsky

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  1. K. D. Chaprov
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Statement on the welfare of animals. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Experiments were carried out in compliance with Order no. 199n “On the Approval of Good Laboratory Practice Guidelines” dated April 1, 2016 of the Ministry of Health of the Russian Federation.

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Translated by T. Tkacheva

Abbreviations: PD, Parkinson’s disease; DN, dopaminergic neuron; SN, substantia nigra; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

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Chaprov, K.D., Teterina, E.V., Roman, A.Y. et al. Comparative Analysis of MPTP Neurotoxicity in Mice with a Constitutive Knockout of the α-Synuclein Gene. Mol Biol 55, 133–142 (2021). https://doi.org/10.1134/S0026893321010039

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