Excess protein synthesis in FXS patient lymphoblastoid cells can be rescued with a p110β-selective inhibitor

Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Molecular Medicine (Impact Factor: 4.51). 12/2011; 18(1):336-45. DOI: 10.2119/molmed.2011.00363
Source: PubMed


The fragile X mental retardation protein (FMRP) plays a key role for neurotransmitter-mediated signaling upstream of neuronal protein synthesis. Functional loss of FMRP causes the inherited intellectual disability fragile X syndrome (FXS), and leads to increased and stimulus-insensitive neuronal protein synthesis in FXS animal models. Previous studies suggested that excess protein synthesis mediated by dysregulated signal transduction contributes to the majority of neurological defects in FXS, and might be a promising target for therapeutic strategies in patients. However, possible impairments in receptor-dependent protein synthesis have not been evaluated in patient cells so far. Using quantitative fluorescent metabolic labeling, we demonstrate that protein synthesis is exaggerated and cannot be further increased by cytokine stimulation in human fragile X lymphoblastoid cells. Our previous work suggested that loss of FMRP-mediated regulation of protein expression and enzymatic function of the PI3K catalytic subunit p110β contributes to dysregulated protein synthesis in a mouse model of FXS. Here, we demonstrate that these molecular mechanisms are recapitulated in FXS patient cells. Furthermore, we show that treatment with a p110β-selective antagonist rescues excess protein synthesis in synaptoneurosomes from an FXS mouse model and in patient cells. Our work suggests that dys-regulated protein synthesis and PI3K activity in patient cells might be suitable biomarkers to quantify the efficacy of drugs to ameliorate molecular mechanisms underlying FXS, and could be used for drug screens to refine treatment strategies for individual patients. Moreover, we provide rationale to pursue p110β-targeting treatments as potential therapy in FXS, and possibly other autism spectrum disorders.

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    • "). AFQ056 was found to be able to correct aberrant hippocampal dendritic spine morphology (Levenga et al., 2011; Pop et al., 2014), and rescue deficits in prepulse inhibition of acoustic startle response and abnormal social behaviors (Levenga et al., 2011; Gantois et al., 2013) in Fmr1 knockout mice. Treatment with mGluR1 antagonists (JNJ16259685 or LY367385) decreased repetitive and/or perseverative behaviors (Thomas et al., 2012), and rescued dysregulated synaptic protein synthesis in fragile X mice (Gross et al., 2010; Guo et al., 2012). These preclinical studies have been paving the way for treatments with mGluR antagonists in humans. "
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    • "Moreover, a duplication in the gene locus of p110β, PIK3CB, most likely leading to enhanced p110β-mediated PI3K activity, has been associated with autism (Cusco et al., 2009), further supporting an essential role of p110β expression in neuronal function. A p110β-selective inhibitor reduced the elevated protein synthesis rates in FXS mice and FXS patient cells suggesting that p110β has a crucial function to control neuronal protein synthesis (Gross and Bassell, 2012), and may be a promising therapeutic target for FXS and other autism spectrum disorders. However, more work is needed to assess the role of p110β and other p110 subunits in neuronal protein synthesis regulation and how this may be altered in human disease. "
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    • "Studies in peripheral cells, such as lymphoblastoid cell lines (LCL), have been successfully employed to study dysregulation of protein expression in ASD [33]. In a systematic review Rossignol and Frye reported studies in LCLs that monitored abnormalities in ASD within distinct pathways, with the strongest evidence for immune dysregulation/inflammation and oxidative stress [34]. "
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