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

Broca-Brisson, L; Harati, R; Disdier, C; Mozner, O; Gaston-Breton, R; Maïza, A; Costa, N; ... Mabondzo, A; + view all (2023) Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency. eLife , 12 , Article RP88459. 10.7554/eLife.88459. Green open access

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Abstract

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.

Type: Article
Title: Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.88459
Publisher version: https://doi.org/10.7554/eLife.88459.3
Language: English
Additional information: © 2023, Broca-Brisson et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: brain, cell biology, cortex, human, neurogenesis, neuroscience, Humans, Intellectual Disability, Creatine, Glycogen Synthase Kinase 3 beta, Mental Retardation, X-Linked, Brain, Organoids
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10181627
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