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

Autor:	Broca-Brisson L; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, France., Harati R; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates., Disdier C; CERES BRAIN Therapeutics, Paris, France., Mozner O; Institute of Enzymology, Research Centre for Natural Sciences, ELKH, and Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary., Gaston-Breton R; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, France., Maïza A; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, France., Costa N; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, France., Guyot AC; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, France., Sarkadi B; Institute of Enzymology, Research Centre for Natural Sciences, ELKH, and Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary., Apati A; Institute of Enzymology, Research Centre for Natural Sciences, ELKH, and Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary., Skelton MR; Department of Pediatrics, University of Cincinnati College of Medicine and Division of Neurology, Cincinnati Children's Research Foundation, Cincinnati, United States., Madrange L; SupBiotech/Service d'Etude des Prions et des Infections Atypiques (SEPIA), Institut François Jacob, CEA, Université Paris Saclay, Paris, France., Yates F; SupBiotech/Service d'Etude des Prions et des Infections Atypiques (SEPIA), Institut François Jacob, CEA, Université Paris Saclay, Paris, France., Armengaud J; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, Bagnols-sur-Cèze, France., Hamoudi R; Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.; Division of Surgery and Interventional Science, University College London, London, United Kingdom.; ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah, United Arab Emirates., Mabondzo A; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, France.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Oct 13; Vol. 12. Date of Electronic Publication: 2023 Oct 13.
DOI:	10.7554/eLife.88459
Abstrakt:	Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy. Competing Interests: LB, RH, CD, OM, RG, AM, NC, AG, BS, AA, MS, LM, FY, JA, RH, AM No competing interests declared (© 2023, Broca-Brisson et al.)
Databáze:	MEDLINE
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