Early dysregulation of GSK3β impairs mitochondrial activity in Fragile X Syndrome

Giulia Cencelli; Giorgia Pedini; Carlotta Ricci; Eleonora Rosina; Giorgia Cecchetti; Antonietta Gentile; Giuseppe Aiello; Laura Pacini; Beatrice Garrone; Rosella Ombrato; Isabella Coletta; Federica Prati; Claudio Milanese; Claudia Bagni

Neurobiology of Disease (Dec 2024)

Early dysregulation of GSK3β impairs mitochondrial activity in Fragile X Syndrome

Giulia Cencelli,
Giorgia Pedini,
Carlotta Ricci,
Eleonora Rosina,
Giorgia Cecchetti,
Antonietta Gentile,
Giuseppe Aiello,
Laura Pacini,
Beatrice Garrone,
Rosella Ombrato,
Isabella Coletta,
Federica Prati,
Claudio Milanese,
Claudia Bagni

Affiliations

Giulia Cencelli: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Giorgia Pedini: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Carlotta Ricci: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Eleonora Rosina: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Giorgia Cecchetti: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Antonietta Gentile: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Giuseppe Aiello: Department of Fundamental Neurosciences, University of Lausanne, 1005 Lausanne, Switzerland
Laura Pacini: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; Faculty of Medicine, UniCamillus, Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy
Beatrice Garrone: Angelini Pharma S.p.A., 00181 Rome, Italy
Rosella Ombrato: Angelini Pharma S.p.A., 00181 Rome, Italy
Isabella Coletta: Angelini Pharma S.p.A., 00181 Rome, Italy
Federica Prati: Angelini Pharma S.p.A., 00181 Rome, Italy
Claudio Milanese: Angelini Pharma S.p.A., 00181 Rome, Italy
Claudia Bagni: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Fundamental Neurosciences, University of Lausanne, 1005 Lausanne, Switzerland; Corresponding author at: Department of Fundamental Neurosciences, University of Lausanne, 1005 Lausanne, Switzerland

Journal volume & issue: Vol. 203
p. 106726

Abstract

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The finely tuned regulation of mitochondria activity is essential for proper brain development. Fragile X Syndrome (FXS), the leading cause of inherited intellectual disability, is a neurodevelopmental disorder in which mitochondrial dysfunction has been increasingly implicated. This study investigates the role of Glycogen Synthase Kinase 3β (GSK3β) in FXS. Several studies have reported the dysregulation of GSK3β in FXS, and its role in mitochondrial function is also well established. However, the link between disrupted GSK3β activity and mitochondrial dysfunction in FXS remains unexplored. Utilizing Fmr1 knockout (KO) mice and human cell lines from individuals with FXS, we uncovered a developmental window where dysregulated GSK3β activity disrupts mitochondrial function. Notably, a partial inhibition of GSK3β activity in FXS fibroblasts from young individuals rescues the observed mitochondrial defects, suggesting that targeting GSK3β in the early stages may offer therapeutic benefits for this condition.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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