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

• Published in: Neurobiology of disease Vol. 154; p. 105338
• Main Authors: Di Marco, B., Dell'Albani, P., D'Antoni, S., Spatuzza, M., Bonaccorso, C.M., Musumeci, S.A., Drago, F., Bardoni, B., Catania, M.V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021; Elsevier
• Subjects: Animals; Animals, Newborn; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Cells, Cultured; eIF2alpha; FMRP; Fragile X Mental Retardation Protein - antagonists & inhibitors; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; mGlu5 receptor; Mice; Mice, Knockout; Oxidative Stress - physiology; Receptor, Metabotropic Glutamate 5 - genetics; Receptor, Metabotropic Glutamate 5 - metabolism; Stress granules; Stress Granules - metabolism; Stress Granules - pathology; FXS; mGlu5 receptor; mGlu receptors; FMRP; Astrocytes; FMR1; MPEP; mRNPs; eIF2alpha; EDTA; Stress granules; PMSF; NaAsO2; Fragile X syndrome; DHPG; ID; NAM; SGs
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105338

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. •Fmr1 KO astrocytes exhibit a reduced number of SGs than WT astrocytes.•mGlu5 activation prior stress lessens SGs and phospho-eIF2α in WT astrocytes.•mGlu5 activation reduces FMRP recruitment in SGs in WT astrocytes.•mGlu5 activation does not affect SG formation in Fmr1 KO astrocytes.•mGlu5 negative allosteric modulation rescues SGs formation in Fmr1 KO astrocytes.