SUMMARYFragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS pheno-types. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1 −/y), we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1 −/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
Fragile X syndrome is the leading monogenic cause of ASD. Trinucleotide repeats in the FMR1 gene abolish FMRP protein expression, leading to hyperactivation of ERK and mTOR signaling, upstream of mRNA translation. Here we show that metformin, the most widely used anti-type 2 diabetes drug, rescues core phenotypes in Fmr1-/y mice and selectively normalizes Erk signaling, Eif4e phosphorylation and the expression of Mmp9. Thus, metformin is a potential FXS therapeutic. Dysregulated mRNA translation is linked to core pathologies diagnosed in the Fragile X neurodevelopmental Syndrome (FXS), such as social and behavior problems, developmental delays and learning disabilities 1,2. In the brains of FXS patients and knockout mice (Fmr1-/y ; X-linked Fmr1 deletion in male mice), loss of Fragile X mental retardation protein (FMRP) results in hyperactivation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and the extracellular signal-regulated kinase (ERK) signaling pathways 1,2. Consistent with increased ERK activity, eukaryotic initiation factor 4E (eIF4E) phosphorylation is elevated in the brain of FXS patients and Fmr1-/y mice, thereby promoting translation of the mRNA encoding for matrix metalloproteinase 9 (MMP-9), which is elevated in the brains of both FXS patients and the Fmr1-/y mice 1-5. In accordance with these findings, knockout of Mmp9 rescues the majority of phenotypes in Fmr1-/y mice. MMP-9 degrades components of the extracellular matrix, including proteins important for synaptic function and maturation, which are implicated in FXS and autism spectrum disorders (ASD). Recent observations indicate that metformin, a first-line therapy for type 2 diabetes, imparts numerous health benefits beyond its original therapeutic use, such as decreased cancer risk and improved cancer prognosis 6. Metformin inhibits the mitochondrial respiratory chain complex 1, leading to a decrease in cellular energy state and thus activation of the energy sensor AMP-activated protein kinase (AMPK) 6. Several AMPK-independent activities of metformin have also been reported 7,8. Since metformin suppresses translation by inhibiting
The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2–/–fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.
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