IJMS, Vol. 24, Pages 9095: Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster


IJMS, Vol. 24, Pages 9095: Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster

International Journal of Molecular Sciences doi: 10.3390/ijms24109095

Yulia S. Vershinina
George S. Krasnov
David G. Garbuz
Mikhail V. Shaposhnikov
Maria S. Fedorova
Elena A. Pudova
Irina V. Katunina
Alexey B. Kornev
Nadezhda V. Zemskaya
Alexander A. Kudryavtsev
Elizaveta V. Bulavkina
Anna A. Matveeva
Natalia S. Ulyasheva
Zulfiya G. Guvatova
Artemiy A. Anurov
Alexey A. Moskalev
Anna V. Kudryavtseva

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 μM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration.

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