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Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome.
Utami, Kagistia Hana; Skotte, Niels H; Colaço, Ana R; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han-Gyu; Garcia-Miralles, Marta; Radulescu, Carola I; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Peteri, Ulla-Kaisa A; Sampath, Prabha; Castrén, Maija L; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud A.
Afiliación
  • Utami KH; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Skotte NH; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark.
  • Colaço AR; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark.
  • Yusof NABM; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Sim B; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Yeo XY; Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Bae HG; Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Garcia-Miralles M; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Radulescu CI; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore; UK Dementia Research Institute, Department of Brain Sciences, Imperial College London, London, United Kingdom.
  • Chen Q; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Chaldaiopoulou G; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Liany H; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Nama S; Institute of Medical Biology, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Peteri UA; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Sampath P; Institute of Medical Biology, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore.
  • Castrén ML; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Jung S; Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Mann M; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark.
  • Pouladi MA; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A∗STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National Un
Biol Psychiatry ; 88(6): 500-511, 2020 09 15.
Article en En | MEDLINE | ID: mdl-32653109
BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking. METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology. RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells. CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Trastorno del Espectro Autista / Síndrome del Cromosoma X Frágil Límite: Humans Idioma: En Revista: Biol Psychiatry Año: 2020 Tipo del documento: Article País de afiliación: Singapur

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Trastorno del Espectro Autista / Síndrome del Cromosoma X Frágil Límite: Humans Idioma: En Revista: Biol Psychiatry Año: 2020 Tipo del documento: Article País de afiliación: Singapur