Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency

• DOI: 10.7554/elife.88459.3
• Publication Date: 2023-10-13T13:35:40Z
• Authors: Léa Broca-Brisson; Rania Harati; Clémence Disdier; Orsolya Mozner; Romane Gaston-Breton; Auriane Maïza; Narciso Costa; Anne-Cécile Guyot; Balazs Sarkadi; Agota Apati; Matthew R Skelton; Lucie Madrange; Frank Yates; Jean Armengaud; Rifat Hamoudi; Aloïse Mabondzo
• Keywords: Creatine; Human brain; CTD

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake brain results intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human organoids from induced pluripotent stem cells of healthy subjects CTD patients. Brain donors had reduced compared with those donors. expression neural progenitor cell markers SOX2 PAX6 was CTD-derived organoids, while GSK3β, a key regulator neurogenesis, up-regulated. Shotgun proteomics combined integrative bioinformatic statistical analysis identified changes abundance proteins associated epilepsy, autism. Re-establishment functional restored normalized SOX2, other clinical features Our organoid model opens new avenues for further characterizing pathophysiology supports concept that reinstating levels patients could result therapeutic efficacy.