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Molecular Medicine

, Volume 18, Issue 3, pp 336–345 | Cite as

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

  • Christina Gross
  • Gary J. Bassell
Research Article

Abstract

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 dysregulated 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.

Notes

Acknowledgments

The authors would like to thank M Kim and A Poopal for excellent technical assistance, and J Mowrey for valuable advice on LCL culturing. Lymphoblastoid cell lines from FXS patients and healthy controls were a kind gift from S Warren (Emory University). The authors thank S Warren for helpful discussions. The authors thank S Swanger for critically reading the manuscript, and all members of the Bassell lab for helpful discussions. This work was supported by a postdoctoral fellowship from FRAXA (to C Gross), the NIH Grant MH085617 (to GJ Bassell), the Emory/Baylor Fragile X Center Grant 3P30HD024064 (to GJ Bassell), and a Suzanne and Bob Wright Trailblazer Award form Autism Speaks (to GJ Bassell).

Supplementary material

10020_2012_1803336_MOESM1_ESM.pdf (795 kb)
Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

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Authors and Affiliations

  1. 1.Emory University School of MedicineAtlantaUSA
  2. 2.Emory University School of MedicineAtlantaUSA
  3. 3.Emory University School of MedicineAtlantaUSA

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