Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i>
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 concentrat...
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MDPI AG
2023-05-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Yulia S. Vershinina |
| collection | DOAJ |
| description | 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 <i>D. melanogaster</i> heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included <i>D. melanogaster</i> 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 <i>D. melanogaster</i> 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 <i>Srr</i> 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. |
| first_indexed | 2024-03-11T03:38:54Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:38:54Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bd674ea862c34a8e93ec94f5976266292023-11-18T01:47:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410909510.3390/ijms24109095Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i>Yulia S. Vershinina0George S. Krasnov1David G. Garbuz2Mikhail V. Shaposhnikov3Maria S. Fedorova4Elena A. Pudova5Irina V. Katunina6Alexey B. Kornev7Nadezhda V. Zemskaya8Alexander A. Kudryavtsev9Elizaveta V. Bulavkina10Anna A. Matveeva11Natalia S. Ulyasheva12Zulfiya G. Guvatova13Artemiy A. Anurov14Alexey A. Moskalev15Anna V. Kudryavtseva16Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaInstitute of Biology, Komi Science Center, Ural Branch of RAS, 167000 Syktyvkar, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaInstitute of Biology, Komi Science Center, Ural Branch of RAS, 167000 Syktyvkar, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaInstitute of Biology, Komi Science Center, Ural Branch of RAS, 167000 Syktyvkar, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaTorin-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 <i>D. melanogaster</i> heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included <i>D. melanogaster</i> 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 <i>D. melanogaster</i> 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 <i>Srr</i> 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.https://www.mdpi.com/1422-0067/24/10/9095RNA-SeqTORneurodegenerationneuroprotectionTorin-2 |
| spellingShingle | 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 Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i> International Journal of Molecular Sciences RNA-Seq TOR neurodegeneration neuroprotection Torin-2 |
| title | Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i> |
| title_full | Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i> |
| title_fullStr | Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i> |
| title_full_unstemmed | Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i> |
| title_short | Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i> |
| title_sort | transcriptomic analysis of the effect of torin 2 on the central nervous system of i drosophila melanogaster i |
| topic | RNA-Seq TOR neurodegeneration neuroprotection Torin-2 |
| url | https://www.mdpi.com/1422-0067/24/10/9095 |
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