Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids

Leigh syndrome (Leigh) is an untreatable mitochondrial disorder characterized by lactic acidosis and basal ganglia and midbrain pathology, leading to psychomotor regression and early death. We previously uncovered impaired neuronal morphogenesis in Leigh cerebral organoids carrying SURF1 gene variants. Leveraging this phenotype, we here develop a deep learning algorithm tailored for cell type-specific drug repurposing screening. In parallel, we perform a survival drug screen in a yeast model of Leigh. The two approaches independently converge on azole compounds, two of which - talarozole and sertaconazole - rescue neuronal morphogenesis in Leigh neurons and lower lactate release and improve growth rate in Leigh midbrain organoids. Mechanistically, these compounds modulate the retinoic acid pathway and membrane-associate lipid metabolism. The findings highlight azoles as promising candidates for Leigh and demonstrate the potential of combining in silico screens with human brain organoids as new approach methodologies (NAMs) to advance the discovery of therapeutics addressing rare neurodevelopmental disorders.

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Journal
Nature Communications
Published
2026-04-20
DOI
https://doi.org/10.1038/s41467-026-71391-2
Citations
1
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
11.27
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Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids

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Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids

Alessandro Prigione, Christine R. Rose, Natascia Ventura, Ethan Perlstein, Felix Distelmaier, Ian Holt, Antonella Spinazzola, Francesc X. Soriano, Mikel Muñoz‐Oreja, Emma Puighermanal, Andrea Zaliani, Tancredi Massimo Pentimalli, Mario Lopez Martin, Satoshi Okawa, Iris Álvarez‐Merz, Gizem Inak, Kasey Woleben, Carmen Menacho, Justin Donnelly, Markus Schuelke, Agnieszka Rybak‐Wolf, Susanne Brodesser, Alex Perálvarez‐Marín, Shiri Zakin, Annika Wittich, Nikolaus Rajewsky, Antonio del Sol, Barbara Mlody, Ole Pleß, Annette Seibt, Selene Lickfett, Mathuravani A. Thevandavakkam, Andrea Rossi, Laura Petersilie, Caleb Jerred, Pawel Lisowski, Jose C. Fernandez-Checa, Sidney Cambridge, Diran Herebian, Ertan Mayatepek
article en
1 citations

Abstract

Leigh syndrome (Leigh) is an untreatable mitochondrial disorder characterized by lactic acidosis and basal ganglia and midbrain pathology, leading to psychomotor regression and early death. We previously uncovered impaired neuronal morphogenesis in Leigh cerebral organoids carrying SURF1 gene variants. Leveraging this phenotype, we here develop a deep learning algorithm tailored for cell type-specific drug repurposing screening. In parallel, we perform a survival drug screen in a yeast model of Leigh. The two approaches independently converge on azole compounds, two of which - talarozole and sertaconazole - rescue neuronal morphogenesis in Leigh neurons and lower lactate release and improve growth rate in Leigh midbrain organoids. Mechanistically, these compounds modulate the retinoic acid pathway and membrane-associate lipid metabolism. The findings highlight azoles as promising candidates for Leigh and demonstrate the potential of combining in silico screens with human brain organoids as new approach methodologies (NAMs) to advance the discovery of therapeutics addressing rare neurodevelopmental disorders.

Nature CommunicationsVol. 17(1)
Ikerbasque (ES), University of Southern California (US), Universitat Autònoma de Barcelona (ES), Mitsubishi Corporation (United States) (US), University of the Basque Country (ES), University of Pittsburgh (US), University of Cologne (DE), University of Luxembourg (LU), Johannes Gutenberg University Mainz (DE), Max Delbrück Center (DE), The Royal Free Hospital (GB), German Center for Neurodegenerative Diseases (DE), San Raffaele University of Rome (IT), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Düsseldorf University Hospital (DE), MSB Medical School Berlin (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), Cenix BioScience (Germany) (DE), Leibniz Institute of Environmental Medicine (DE), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), National Center for Tumor Diseases (DE), CIC bioGUNE (ES), Centro de Investigación Biomédica en Red (ES), Institute for Research in Biomedicine (ES), Institut d'Investigacions Biomèdiques de Barcelona (ES), German Centre for Cardiovascular Research (DE), Centogene (Germany) (DE), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), National Hospital for Neurology and Neurosurgery (GB), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Deutsches Konsortium für Translationale Krebsforschung (DE), Heinrich Heine University Düsseldorf (DE), University College London (GB), Universitat de Barcelona (ES), Charité - Universitätsmedizin Berlin (DE), Polish Academy of Sciences (PL)
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Mitochondrial Function and Pathology
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