Positive feedback regulation of Akt-FMRP pathway protects neurons from cell death

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism spectrum disorder, linked to FMR1 gene mutations.
• The FMR1 gene encodes fragile X mental retardation protein (FMRP), crucial for neuronal development and synapse formation by regulating mRNA translation.
• FMRP's role in neuronal cell viability, particularly under stress conditions, requires further investigation.

Purpose of the Study:

• To investigate the role of FMRP in neuronal cell viability under conditions of excitotoxicity and ischemia.
• To determine the molecular mechanisms, including the involvement of the PI3K/Akt pathway, underlying FMRP's effect on cell survival.

Main Methods:

• Induction of apoptosis in rat primary cortical neurons using glutamate (in vitro) and in striatal neurons via middle cerebral artery occlusion (MCAO) (in vivo).
• Assessment of FMRP expression levels and its regulation by PI3K/Akt pathway inhibitors (LY294002, Akt inhibitor IV, VIII).
• Manipulation of FMRP levels using small hairpin Fmr1 virus (reduction) and eGFP-FMRP constructs (over-expression) to evaluate effects on cell death, Akt activity, and Bcl-xL expression.

Main Results:

• Glutamate and MCAO induced a rapid, transient up-regulation of FMRP expression in neurons.
• Inhibition of PI3K and Akt pathways abolished the FMRP up-regulation.
• Reduced FMRP exacerbated neuronal death, while FMRP over-expression protected neurons, increased Akt activity, and enhanced Bcl-xL production.

Conclusions:

• FMRP plays a significant pro-survival role in neurons, particularly under excitotoxic and ischemic stress.
• Akt-dependent up-regulation of FMRP contributes to neuronal protection.
• These findings suggest potential therapeutic strategies targeting the FMRP-Akt pathway for FXS, neurodegenerative diseases, and traumatic brain injury.