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

NEUROBIOLOGY OF DISEASE

卷:154

Article

Di Marco, B.^1,5  Dell'Albani, P.¹  D'Antoni, S.¹  Spatuzza, M.^2,6  Bonaccorso, C. M.²  Musumeci, S. A.²  Drago, F.³  Bardoni, B.⁴  Catania, M. V.^1,2 

[1] Natl Res Council Italy IRIB CNR, Inst Biomed Res & Innovat, Via Paolo Gaifami 18, I-95126 Catania, Italy

[2] Oasi Res Inst IRCCS, Troina, Italy

[3] Univ Catania, Dept Biomed & Biotecnol Sci, Catania, Italy

[4] Univ Cote Azur, INSERM, CNRS UMR7275, Inst Mol & Cellular Pharmacol, F-06560 Valbonne, France

[5] German Canc Res Ctr, Dept Clin Neurobiol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[6] Natl Res Council Italy, Inst Biomed Res & Innovat IRIB, Catania, Italy

关键词: Stress granules;    mGlu5 receptor;    FMRP;    Fragile X syndrome;    eIF2alpha;    Astrocytes;   

DOI  :  10.1016/j.nbd.2021.105338

来源: Elsevier

【 摘 要 】

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 eIF2?, 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.