Title: Loss of RACK1 regulation by FMRP contributes to electrophysiological and mitochondrial deficits in human Fragile X Syndrome neurons
Abstract: Regulation of hundreds of different mRNAs by Fragile X Messenger Ribonucleoprotein 1 Protein (FMRP) is essential to normal cortical development and function, the loss of which contributes to the etiology of Fragile X Syndrome (FXS). While much effort has been spent identifying and validating FMRP’s mRNA targets in animal models and non-neuronal cell types, identification of human-specific FMRP targets in disease-relevant subtypes is important for the discovery of translational therapeutic targets. In this study, we showed that FMRP is important for human prenatal brain development. FMRP-deficient neurons and FXS patient stem cell-derived neurons both exhibited mitochondrial dysfunctions and hyperexcitability, and using multiomic analyses, we identified FMRP-bound mRNAs and FMRP-interacting proteins in human neurons. We demonstrated that FMRP’s interaction with CCR4-NOT transcription complex subunit 1 (CNOT1) maintains the levels of Receptor for Activated C Kinase 1 (RACK1), a species-specific FMRP mRNA target. Genetic reduction of RACK1 lead to both mitochondrial dysfunction and hyperexcitability, resembling FXS neurons, and restoration of RACK1 rescued deficits of human FXS neurons. Finally, enhancing mitochondrial functions using a small molecule rescued deficits of FMRP-deficient cortical neurons, demonstrating that rescuing mitochondrial dysfunction is a potential therapeutic target in FXS.
The Seminar is held each Tuesday during the semester from noon-1 p.m.
This event is offered in a hybrid format:
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- *if you are asked for a passcode: 970506
- https://uwmadison.zoom.us/j/96958883460