Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion

Article Article scientifique Article Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion eng 2026-03-06 author Maletic Marina Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France. author Bizzotto Sara Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France.,Université Paris Cité, Imagine Institute, 75015 Paris, France. author Ribierre Théo Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France.,Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland.,NeuroNA Human Cellular Neuroscience Platform, Fondation Campus Biotech Geneva, 1205 Geneva, Switzerland. 958680 author Guerdoud Kenza Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France. author Raoux Corentin Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France. author Doladilhe Marion Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France. author Dalle Carine Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France. author Picard Fabienne Department of Clinical Neurosciences, University Hospitals and Medical School of Geneva, 1205 Geneva, Switzerland. 123049 Département des neurosciences cliniques (OTONO) author Baulac Stéphanie 0000-0001-6430-4693 Sorbonne Université, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France. awag086 10.1093/brain/awag086 41789478 0006-8950 https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awag086 Focal cortical dysplasia type II (FCDII), a major cause of pediatric drug-resistant focal epilepsy, results from brain somatic variants in mTOR pathway genes, including germline and somatic second-hit loss-of-function variants in the mTOR repressor DEPDC5. Here, we present a proof-of-concept model of DEPDC5 two-hit inactivation mosaicism using patient-derived human cortical organoids (hCOs). Mosaic hCOs displayed increased mTOR activity that was rescued by the mTOR inhibitor rapamycin. Mosaic hCOs also exhibited dysmorphic-like neurons and enhanced neuronal excitability, recapitulating key FCDII pathology hallmarks. Single-cell transcriptomics across three developmental stages revealed aberrant differentiation trajectories leading to premature upper-layer neuron generation, upregulated Notch and Wnt signaling pathways in neural progenitors, and altered expression of synaptic- and epilepsy-associated genes in excitatory neurons. In addition, we identified cell-autonomous alterations in metabolism and translation in mosaic DEPDC5 two-hit hCOs. This study provides novel insights into how DEPDC5 deficiency perturbs human corticogenesis, highlighting that mosaic biallelic inactivation of the gene is necessary for FCDII pathogenesis. Brain mosaicism Epilepsy Focal cortical dysplasia MTOR signaling Neurodevelopmental disorders Somatic mutations Dewey 616.8 European Commission NEUROBIOLOGY OF EPILEPSY GENES 682345 EPITOR EU H2020 ANR program "Investissements d'avenir" ANR-10-IAIHU-06 Fondation pour la Recherche Médicale ECO20160736027 ANR ERANET-NEURON ANR-21-NEU2-0002-01 European Commission Exploring new genetic causes and pathological mechanisms of epileptic focal cortical dysplasia 101026484 CODICES EU H2020 European Commission Lineage tracing of the human brain 101115984 LINMOS EU HE Fondation pour la Recherche Médicale FDT201904008269 61 Département des neurosciences cliniques 226 false Brain 63bae6bd-4619-43fb-bdbf-442e4bc2df7e Article (Accepted version) Public awag086.pdf 3548726 application/pdf CC BY-NC-4.0 c0c3b00f7a6094269420d7c1e3915df71771e16aeaa2bbbc43072453f1440f8f d8f7cb49-4ec6-4bc0-a7b7-962b9be38dfa Supplemental data Public brain-2025-01505-File010.pdf 3650076 application/pdf 1cadfcddf9ec427e94b31e11db2a79b663a62171e2a758d217be81dae54ded47 1d43a5f7-d715-48bd-bd5e-81b7ffb31016 Supplemental data Public brain-2025-01505-File011.xlsx 483719 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 61f4df16ab69dda9a7ea8fe094e2f1e854c03729184422da0207667559cc4ac0 61d38823-d63c-4500-b9fa-1f973546a55f Supplemental data Public brain-2025-01505-File012.xlsx 1211568 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 3929a461e621fc7bcf47f6c7f40216caec769edaf4f2bc356113dd652f9b944a c33cde39-02d6-4c24-9ece-9bd6d8a4abb2 Supplemental data Public brain-2025-01505-File013.xlsx 511345 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 822896e8a18d77c673d60248f1e200f0ce70670514f81e46e5008f01411650d2 70fdc06d-20f2-408e-9dc0-8c82f87141e3 Supplemental data Public brain-2025-01505-File014.xlsx 178412 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet bc7296d889723ce883abe9bb74be235716482e8c2020e77e1eaf47f36347ad50 aab3a114-3bb5-416f-bc04-c44d7d8251e9 Supplemental data Public brain-2025-01505-File015.xlsx 37320 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 3f54e33c2790eb93888d578a46573b133287c4ade6e7dbd849e6ebfe1c34d8b8 1bc78490-c2f8-4e05-a0a1-fa84a7082099 Supplemental data Public brain-2025-01505-File016.xlsx 509605 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet b6e4b06700072587ffd31b5dad540e700f268bd72274090a9d431a469cb52aaf ad033eab-8601-4377-b8ef-4c1140e46c65 Supplemental data Public brain-2025-01505-File017.xlsx 223095 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 7adfb0b8f5c951f1fae3f084ea36daecf9b7951628ac827b7bd72d89529e91e8 openAccess Faculté de médecine / Section de médecine clinique / Département des neurosciences cliniques

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion	Brain			2026	1	0

Archive ouverte UNIGE

Ribierre, Théo