Effects of Prenatal Hyperhomocysteinemia on Autophagy and mTOR Signaling In The Developing Rat Brain

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Abstract

Autophagy and mTOR signaling are fundamental mechanisms that regulate cellular homeostasis and neurogenesis. Alterations in these processes are associated with cognitive dysfunctions and abnormalities in the formation of various brain structures, which are also observed in offspring after prenatal hyperhomocysteinemia (HHCy). In this study, we investigated the potential impact of maternal HHCy on the activity of autophagy and the mTOR signaling pathway in the brains of fetuses and offspring. The data obtained demonstrate the absence of significant changes in the levels of mTOR and its phosphorylated form (p-mTOR), as well as key effector proteins (rpS6, p-rpS6, 4E-BP1 and p-4E-BP1) in the fetal brain at the early embryonic (14th day of development, E14) stages of development and in postnatal ontogenesis (5th and 20th days of life, P5 and P20) in the parietal cortex of rats, with the exception of the late embryonic period (E20), which is characterized by a decrease in the level of 4E-BP1 and p-rpS6 (Ser235/236) during maternal death induced by methionine loading. The levels of markers of the main stages of autophagy (ATG13, Beclin-1, Ambra-1, LC3B, p62, LAMP-2) did not change in the embryonic brain (E14 and E20) and the parietal cortex of early postnatal animals (P5), and there was no significant increase in the number of autophagolysosomes and lysosomes in the HCCy. However, an increase in the number of lysosomes, but not autophagosomes, in the parietal cortex of the P20 brain in animals after prenatal HCCy may be associated with an increase in lysosomal biogenesis. Therefore, the canonical mTOR-dependent change in autophagy in the fetal brain and the parietal cortex of the offspring after moderate methionine-induced HCCy in the mother is not a significant mechanism for the negative impact on brain tissue formation.

About the authors

A. V. Mikhel

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive medicine; I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: anastasia.michel39@gmail.com
St. Petersburg, Russia; St. Petersburg, Russia

D. S. Vasilev

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive medicine; I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

St. Petersburg, Russia; St. Petersburg, Russia

A. V. Gorbova

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive medicine

St. Petersburg, Russia

Y. P. Milyutina

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive medicine

St. Petersburg, Russia

I. V. Zalozniaia

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive medicine

St. Petersburg, Russia

N. L. Tumanova

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

St. Petersburg, Russia

A. V. Arutjunyan

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive medicine

St. Petersburg, Russia

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