The C886T Mutation in the TH Gene Reduces the Activity of Tyrosine Hydroxylase in the Brain of Mice

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Abstract

Tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine, the initial and rate-limiting step in the synthesis of dopamine, noradrenaline, and adrenaline. Mutations in the human TH gene are associated with hereditary motor disorders. The common C886T mutation identified in the mouse Th gene results in the R278H substitution in the enzyme molecule. We investigated the impact of this mutation on the TH activity in the mouse midbrain. The TH activity in the midbrain of Mus musculus castaneus (CAST) mice homozygous for the 886C allele was higher compared to C57BL/6 and DBA/2 mice homozygous for the 886T allele. Notably, this difference in the enzyme activity was not associated with changes in the Th gene mRNA levels and TH protein content. Analysis of the TH activity in the midbrain in mice from the F2 population obtained by crossbreeding of C57BL/6 and CAST mice revealed that the 886C allele is associated with a high TH activity. Moreover, this allele showed complete dominance over the 886T allele. However, the C886T mutation did not affect the levels of TH protein in the midbrain. These findings demonstrate that the C886T mutation is a major genetic factor determining the activity of TH in the midbrain of common laboratory mouse strains. Moreover, it represents the first common spontaneous mutation in the mouse Th gene whose influence on the enzyme activity has been demonstrated. These results will help to understand the role of TH in the development of adaptive and pathological behavior, elucidate molecular mechanisms regulating the activity of TH, and explore pharmacological agents for modulating its function.

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About the authors

I. Alsallum

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: v_kulikov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

V. S. Moskalyuk

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: v_kulikov@bionet.nsc.ru
Russian Federation, Novosibirsk

I. A. Rakhov

Novosibirsk State University

Email: v_kulikov@bionet.nsc.ru
Russian Federation, Novosibirsk

D. V. Bazovkina

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: v_kulikov@bionet.nsc.ru
Russian Federation, Novosibirsk

A. V. Kulikov

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Author for correspondence.
Email: v_kulikov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

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2. Fig. 1. TH activity (a), Th gene mRNA level (b) and TH protein level (c) in the midbrain of mice of inbred lines C57BL/6 (TT), DBA/2 (TT) and subspecies CAST (CC). Individual values, mean ± errors of the mean are presented. Th gene expression was calibrated to Polr2a gene expression, and TH protein level was calibrated to GAPDH protein level. *** p < 0.001 vs CAST

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3. Fig. 2. TH activity (a) and protein levels (b) in the midbrain of F2 intercrosses with TT, TC and CC genotypes. Data for males and females are pooled. Individual values, mean ± errors of the mean are presented. TH protein levels are calibrated to GAPDH protein levels. * p < 0.05, *** p < 0.001 vs TT

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