Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes.

Abstract

Fragile X syndrome (FXS) is a common form of intellectual disability and autism caused by the lack of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA transport and protein synthesis. Upon cellular stress, global protein synthesis is blocked and mRNAs are recruited into stress granules (SGs), together with RNA-binding proteins including FMRP. Activation of group-I metabotropic glutamate (mGlu) receptors stimulates FMRP-mediated mRNA transport and protein synthesis, but their role in SGs formation is unexplored. To this aim, we pre-treated wild type (WT) and Fmr1 knockout (KO) cultured astrocytes with the group-I-mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) and exposed them to sodium arsenite (NaAsO2), a widely used inducer of SGs formation. In WT cultures the activation of group-I mGlu receptors reduced SGs formation and recruitment of FMRP into SGs, and also attenuated phosphorylation of eIF2α, a key event crucially involved in SGs formation and inhibition of protein synthesis. In contrast, Fmr1 KO astrocytes, which exhibited a lower number of SGs than WT astrocytes, did not respond to agonist stimulation. Interestingly, the mGlu5 receptor negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine (MPEP) antagonized DHPG-mediated SGs reduction in WT and reversed SGs formation in Fmr1 KO cultures. Our findings reveal a novel function of mGlu5 receptor as modulator of SGs formation and open new perspectives for understanding cellular response to stress in FXS pathophysiology.

• Authors: B Di Marco, P Dell'Albani, S D'Antoni, M Spatuzza, C M Bonaccorso, S A Musumeci, F Drago, B Bardoni, M V Catania
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 154 Pg. 105338 (07 2021) ISSN: 1095-953X [Electronic] United States
• PMID: 33775821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Fmr1 protein, mouse
• Grm5 protein, mouse
• Receptor, Metabotropic Glutamate 5
• Fragile X Mental Retardation Protein

Topics

• Animals
• Animals, Newborn
• Astrocytes (metabolism, pathology)
• Cells, Cultured
• Fragile X Mental Retardation Protein (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Knockout
• Oxidative Stress (physiology)
• Receptor, Metabotropic Glutamate 5 (genetics, metabolism)
• Stress Granules (metabolism, pathology)