title: Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome.
abstract: Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 (R306C) and MECP2 (1155Δ32)) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.
authors.affiliation: Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.|Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore.|NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore, 117597, Singapore.
authors.forename: Eunice W M
authors.initials: EW
authors.lastname: Chin
authors.affiliation: Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marcy
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: Su-In
authors.initials: SI
authors.lastname: Yoon
authors.affiliation: Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.|Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ma
authors.affiliation: Abbott Nutrition Research and Development, Columbus, Ohio, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rosales
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. george.augustine@ntu.edu.sg.
authors.forename: George J
authors.initials: GJ
authors.lastname: Augustine
authors.affiliation: Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. eyleen.goh@duke-nus.edu.sg.|Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore. eyleen.goh@duke-nus.edu.sg.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. eyleen.goh@duke-nus.edu.sg.|KK Research Center, KK Women's and Children's Hospital, Singapore, 229899, Singapore. eyleen.goh@duke-nus.edu.sg.
authors.forename: Eyleen L K
authors.identifier: http://orcid.org/0000-0002-8244-6959
authors.initials: EL
authors.lastname: Goh
mesh_terms: D002794:Choline / Q000494:pharmacology*; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D009154:Mutation; D015518:Rett Syndrome / Q000628:therapy*
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D002794:Choline
keywords: ChAT; Choline; Human iPSC; Lipid metabolite profile; MeCP2; Neutraceutical; Rett syndrome; Synaptic functions