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Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes
- Source :
- Neurobiology of disease 154 (2021). doi:10.1016/j.nbd.2021.105338, info:cnr-pdr/source/autori:Di Marco B.; Dell'Albani P.; D'Antoni S.; Spatuzza M.; Bonaccorso C.M.; Musumeci S.A.; Drago F.; Bardoni B.; Catania M.V./titolo:Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes/doi:10.1016%2Fj.nbd.2021.105338/rivista:Neurobiology of disease/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:154, Neurobiology of Disease, Vol 154, Iss, Pp 105338-(2021)
- Publication Year :
- 2021
- Publisher :
- Blackwell Science, Oxford , Regno Unito, 2021.
-
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.
- Subjects :
- 0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Allosteric modulator
Receptor, Metabotropic Glutamate 5
Neurosciences. Biological psychiatry. Neuropsychiatry
Stress granules mGlu5 receptor FMRP Fragile X syndrome eIF2alpha Astrocytes
Fragile X Mental Retardation Protein
Mice
03 medical and health sciences
0302 clinical medicine
Stress granule
stomatognathic system
Animals
MRNA transport
Receptor
Cells, Cultured
Mice, Knockout
Chemistry
Glutamate receptor
FMR1
Stress Granules
Cell biology
Oxidative Stress
030104 developmental biology
Metabotropic receptor
mGlu5 receptor
Animals, Newborn
Neurology
Metabotropic glutamate receptor
Astrocytes
FMRP
eIF2alpha
030217 neurology & neurosurgery
Fragile X syndrome
RC321-571
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Neurobiology of disease 154 (2021). doi:10.1016/j.nbd.2021.105338, info:cnr-pdr/source/autori:Di Marco B.; Dell'Albani P.; D'Antoni S.; Spatuzza M.; Bonaccorso C.M.; Musumeci S.A.; Drago F.; Bardoni B.; Catania M.V./titolo:Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes/doi:10.1016%2Fj.nbd.2021.105338/rivista:Neurobiology of disease/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:154, Neurobiology of Disease, Vol 154, Iss, Pp 105338-(2021)
- Accession number :
- edsair.doi.dedup.....2dec0b289ba02fb2d2045b87d57a7297