Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

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Utami , K H , Skotte , N H , Colaco , A R , Yusof , N A B M , Sim , B , Yeo , X Y , Bae , H-G , Garcia-Miralles , M , Radulescu , C I , Chen , Q , Chaldaiopoulou , G , Liany , H , Nama , S , Peteri , U-K A , Sampath , P , Castrén , M , Jung , S , Mann , M & Pouladi , M 2020 , ' Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome ' , Biological Psychiatry , vol. 88 , no. 6 , pp. 500-511 . https://doi.org/10.1016/j.biopsych.2020.05.005

Title: Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome
Author: Utami, Kagistia Hana; Skotte, Nils H.; Colaco, Ana R.; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han-Gye; Garcia-Miralles, Marta; Radulescu, Carola I.; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Peteri, Ulla-Kaisa A.; Sampath, Prabha; Castrén, Maija; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud
Contributor: University of Helsinki, NeuroDevDiseaseModelling
University of Helsinki, Department of Physiology
Date: 2020-09-15
Language: eng
Number of pages: 12
Belongs to series: Biological Psychiatry
ISSN: 0006-3223
URI: http://hdl.handle.net/10138/333443
Abstract: 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.
Subject: 3112 Neurosciences
1184 Genetics, developmental biology, physiology
Fragile X syndrome
Human neurons
Isogenic
Neurodevelopmental disorders
Proteome
Transcriptome
1182 Biochemistry, cell and molecular biology
Fragile X syndrome
Human neurons
Isogenic
Neurodevelopmental disorders
Proteome
Transcriptome
EMBRYONIC STEM-CELLS
MENTAL-RETARDATION PROTEIN
INTELLECTUAL DISABILITY
SYNDROME NEURONS
MOUSE MODEL
DIFFERENTIATION
GENE
ABNORMALITIES
MECHANISMS
NEUROGENESIS
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