Vershinina, Y.S., Krasnov, G.S., Garbuz, D.G., Shaposhnikov, M.V., Fedorova, M.S., Pudova, E.A., Katunina, I.V., Kornev, A.B., Zemskaya, N.V., Kudryavtsev, A.A., Bulavkina, E.V., Matveeva, A.A., Ulyasheva, N.S., Guvatova, Z.G., Anurov, A.A., Moskalev, A.A., Kudryavtseva, A.V. (2023). Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster.  Int. J. Mol. Sci. 24(10): 9095.

FBrf0256578

Research paper

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.

PMC10219255 (PMC) (EuropePMC)