Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons
Name
ejn.14660.pdf
Description
Accepted version
Size
1.59 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Graef, John D
Wu, Hao
Ng, Carrie
Sun, Chicheng
Villegas, Vivian
Qadir, Deena
Jesseman, Kimberly
Warren, Stephen T
Jaenisch, Rudolf
Cacace, Angela
Date Issued
2020
Journal
European Journal of Neuroscience
Publisher
Wiley
Version
Final published version
Abstract
© 2019 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. Fragile X syndrome (FXS) is the most common genetic form of intellectual disability caused by a CGG repeat expansion in the 5′-UTR of the Fragile X mental retardation gene FMR1, triggering epigenetic silencing and the subsequent absence of the protein, FMRP. Reactivation of FMR1 represents an attractive therapeutic strategy targeting the genetic root cause of FXS. However, largely missing in the FXS field is an understanding of how much FMR1 reactivation is required to rescue FMRP-dependent mutant phenotypes. Here, we utilize FXS patient-derived excitatory neurons to model FXS in vitro and confirm that the absence of FMRP leads to neuronal hyperactivity. We further determined the levels of FMRP and the percentage of FMRP-positive cells necessary to correct this phenotype utilizing a mixed and mosaic neuronal culture system and a combination of CRISPR, antisense and expression technologies to titrate FMRP in FXS and WT neurons. Our data demonstrate that restoration of greater than 5% of overall FMRP expression levels or greater than 20% FMRP-expressing neurons in a mosaic pattern is sufficient to normalize a FMRP-dependent, hyperactive phenotype in FXS iPSC-derived neurons.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1111/EJN.14660
