Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome

Author:

Ren Baiyan1,Burkovetskaya Maria2,Jung Yoosun2,Bergdolt Lara3,Totusek Steven2,Martinez‐Cerdeno Veronica4ORCID,Stauch Kelly2,Korade Zeljka156,Dunaevsky Anna123ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology University of Nebraska Medical Center Omaha Nebraska USA

2. Department of Neurological Sciences University of Nebraska Medical Center Omaha Nebraska USA

3. Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center Omaha Nebraska USA

4. Department of Pathology and Laboratory Medicine MIND Institute, and Institute for Pediatric Regenerative Medicine at UC Davis School of Medicine, and Shriners Hospitals for Children of Northern California Sacramento California USA

5. Munroe‐Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center Omaha Nebraska USA

6. Department of Pediatrics CHRI, College of Medicine, University of Nebraska Medical Center Omaha Nebraska USA

Abstract

AbstractFragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human‐based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human‐based FXS model via differentiation of astrocytes from human‐induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca2+ signaling, impaired sterol biosynthesis, and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.

Funder

National Institute of Neurological Disorders and Stroke

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Neurology

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