LOSS OF FMRP IS ASSOCIATED WITH INCREASED VULNERABILITY TO OXIDATIVE STRESS AND CELLULAR SENESCENCE IN THE MOUSE MODEL OF FRAGILE X SYNDROME

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a leading monogenic cause of autism, caused by mutations in the fragile X mental retardation 1 (FMR1) gene and ensuing lack of fragile X ribonucleoprotein 1 (FMRP), an RNA-binding protein regulating mRNA transport and translation. FMRP absence in the brain alters synaptic protein expression and disrupts neuronal function. The FXS mouse model shows an excess of oxidizing agents in the brain, potentially causing damage to macromolecules, and enhancing susceptibility to cell injury. Oxidative stress can also trigger cellular senescence, which is characterized by secretion of neurotoxic senescence-associated factors. FMRP also participates in the DNA damage response and is a component of stress granules (SGs). However, how neural cells respond to oxidative insults in the absence of FMRP remains poorly understood.
We examined SGs formation and cell survival after exposure to oxidative stress in cultured neurons and astrocytes of wild-type (WT) and Fmr1 knockout (KO) by immunocytochemistry and MTT assay. We also used senescence-associated-b-galactosidase (SA-b-gal) assay and Western blotting to examine markers of senescence in cultured astrocytes and brain regions.
In cultures from Fmr1 KO mice exposed to oxidative stress we detected a lower number of SGs in astrocytes and a lower viability of neurons and astrocytes. Fmr1 KO brains exhibited increased SA-b-gal staining and a different expression of senescent markers.
These results suggest that lack of FMRP sensitizes to oxidative stress-induced damage and accelerates senescence, possibly contributing to brain dysfunction in FXS.
Fondation Lejeune; FOE-2022-INVAT