![]() This strategy rescues behavioral and neurological function in a mouse model of FXS. The third and final approach involves inhibition of eIF4E phosphorylation by MNK using the antifungal phytotoxin natural product, cercosporamide. Defects in memory and spinogenesis are corrected by 4EGI-1 in Fmr1 -/- mice. A second approach involves direct inhibition of the physical interaction between eIF4E and eIF4G with the small molecule 4EGI-1. Metformin resolves behavioral deficits observed in Fmr1-deficient animals. At high doses, metformin blocks 4EBP phosphorylation by mTOR resulting in a decrease of eIF4E availability. Metformin is a translational inhibitor that affects multiple pathways including mTOR. ![]() One strategy to decrease eIF4E levels makes use of the antidiabetic drug, metformin. Multiple pharmacological approaches that modulate eIF4E activity have been applied to FXS. Furthermore, many of the phenotypes observed in Fmr1 −/− animals are rescued through introduction of a single amino acid substitution in eIF4E (S209A) that renders the protein incapable of being phosphorylated by MNK. Genetic reduction of MNK resolves behavioral deficits and restores synaptic activity in Fmr1-deficient animals. Increased levels of eIF4E phosphorylation are correlated with core phenotypes associated with FXS, both in human patients and Fmr1-deficient mice. Loss of FMRP results in elevated levels of eIF4E phosphorylation due to increased MAPK signaling upstream of MNK. The main phosphatase that regulates eIF4E is protein phosphatase 2A. eIF4E is also regulated through dephosphorylation. An additional mechanism that regulates eIF4E is post-translational modification by MNK1 and MNK2 (collectively referred to as MNK) at a single site, S209. Phosphorylation of 4EBP by mechanistic target of rapamycin (mTOR) prevents binding to eIF4E, and thus promotes formation of the eIF4F complex. eIF4E is further regulated by eIF4E binding proteins (4EBPs) that prevent eIF4E from interacting with eIF4G. eIF4E is the least abundant component of eIF4F, and its activity is meticulously controlled. eIF4E reversibly binds to the cap and fosters translation initiation through recruitment of the scaffold eIF4G and the helicase eIF4A forming the tripartite eIF4F complex. Īll mRNAs possess a 5′ cap that enables signal-dependent control of translation initiation. Restoration of translational homeostasis has emerged as a potential means to correct neuronal dysfunction and rescue behavioral deficits associated with FXS. Exaggerated protein synthesis in the brain is a hallmark of FXS and is recapitulated in animal models of Fmr1 deficiency. Multiple targets perform functions linked to synaptic plasticity. FMRP is a polysome-associated RNA-binding protein that governs translation of a large subset of mRNAs. Fmr1 encodes the fragile X mental retardation protein (FMRP). This mutation promotes epigenetic silencing and loss of the corresponding polypeptide. The most common genetic change associated with FXS is a trinucleotide (CGG) expansion in the 5′ untranslated region of the Fmr1 gene. Physiological abnormalities such as circuit hyperexcitability and abnormal spinogenesis are observed in FXS. Affected individuals display numerous behavioral deficits that include deficits in learning and memory, hyperactivity, increased anxiety, impaired social interactions, and repetitive behavioral patterns. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.įragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans and is the leading cause of autism spectrum disorder (ASD). Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans.
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