Xinyu Zhao, PhD – Slide of the Week

Xinyu Zhao, PhD - Slide of the Week

Title: Loss of RACK1 regulation by FMRP contributes to electrophysiological and mitochondrial deficits in human Fragile X Syndrome neurons

Citation: Shen M*, Sirois CL*, Guo Y*, Li, M*, (*equal contribution), Dong Q, Mendez-Albelo NM, Gao Y, Khullar S, Kissel L, Sandoval SO, Wolkoff N, Huang SX, Xu Z, Bryan JE, Contractor A, Korabelnikov T, Glass IA, Doherty D, Birth Defects Research Laboratory, Levine JE, Sousa AMM, Chang Q, Bhattacharyya A, Wang D, Werling DM, and Zhao X. Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development. 2023. Neuron 111 (1-18). doi:10.1016/j.neuron.2023.09.014; PMID: 37820724

Abstract: Fragile X messenger ribonucleoprotein 1 protein (FMRP) deficiency leads to fragile X syndrome (FXS), an autism spectrum disorder. The role of FMRP in prenatal human brain development remains unclear. Here we show that FMRP is important for human and macaque prenatal brain development. Both FMRP-deficient neurons in human fetal cortical slices and FXS patient stem cell-derived neurons exhibit mitochondrial dysfunctions and hyperexcitability. Using multiomics analyses, we have identified both FMRP-bound mRNAs and FMRP-interacting proteins in human neurons and unveiled a previously unknown role of FMRP in regulating essential genes during human prenatal development. We demonstrate that FMRP interaction with CNOT1 maintains the levels of receptor for activated C kinase 1 (RACK1), a species-specific FMRP target. Genetic reduction of RACK1 leads to both mitochondrial dysfunctions and hyperexcitability, resembling FXS neurons. Finally, enhancing mitochondrial functions rescues deficits of FMRP-deficient cortical neurons during prenatal development, demonstrating targeting mitochondrial dysfunction as a potential treatment.

Xinyu Zhao
Xinyu Zhao, PhD

Investigator: Xinyu Zhao, PhD

About the Lab: The Zhao Lab is located at the Waisman Center of University of Wisconsin-Madison, our laboratory is part of the Department of Neuroscience and Stem Cells and Regenerative Medicine Center.  We strive to adapt, develop, and integrate state-of-art approaches to investigate the molecular mechanisms underlying neurogenesis and neuronal development.

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