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| Item Type: | Preprint |
|---|---|
| Title: | Deep learning-driven neuromorphogenesis screenings identify repurposable drugs for mitochondrial disease |
| Creators Name: | Menacho, C., Okawa, S., Alvarez-Merz, I., Wittich, A., Muñoz-Oreja, M., Lisowski, P., Pentimalli, T.M., Rybak-Wolf, A., Inak, G., Zakin, S., Thevandavakkam, M., Petersilie, L., Zaliani, A., Mlody, B., Seibt, A., Donnelly, J., Woleben, K., Fernandez-Checa, J., Herebian, D., Mayatepek, E., Rajewsky, N., Spinazzola, A., Schuelke, M., Perlstein, E., Rossi, A., Distelmaier, F., Holt, I.J., Pless, O., Rose, C., Del Sol, A. and Prigione, A. |
| Abstract: | Mitochondrial disease encompasses untreatable conditions affecting tissues with high energy demands. A severe manifestation of mitochondrial disease is Leigh syndrome (Leigh), which causes defects in basal ganglia and midbrain regions, psychomotor regression, lactic acidosis, and early death. We previously generated isogenic pairs of Leigh cerebral organoids and uncovered defects in neuromorphogenesis. Here, we leveraged on this disease feature to devise drug discovery pipelines. We developed a deep learning algorithm tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. In parallel, we performed a survival drug screen in yeast and validated the repurposable hits on branching capacity in Leigh neurons. The two approaches independently highlighted azole compounds, Talarozole and Sertaconazole, both of which lowered lactate release and improved neurogenesis and neurite organization in Leigh midbrain organoids. Hence, targeting neuromorphogenesis has led to identify potential new drugs for mitochondrial disease and could prove an effective strategy for further drug discovery. |
| Keywords: | Mitochondrial Disease, Leigh Syndrome, Brain Organoids, Neurons, Drug Screening, Morphogenesis |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2024.07.08.602501 |
| Date: | 12 July 2024 |
| Official Publication: | https://doi.org/10.1101/2024.07.08.602501 |
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