Abstract
Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.
Highlights
Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear
Previous publications monitoring new protein synthesis have reported a net increase in S35, puromycin, or azido-homoalanine (AHA) incorporation, suggesting elevated de novo translation in Fmr[1] knockout (KO, FXS model) mice[5,22,23]
When taken alone these criteria for selecting candidates for differential regulation were not statistically stringent enough to ensure high confidence. Proteins that met these criteria were subjected to gene ontology (GO) analysis (Supplementary Data 2), and only those identified as significantly enriched (p < 1E −5 after FDR correction) were considered for further independent verification by western blotting
Summary
Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Basic mechanistic studies have offered valuable insights into FMRP action by focusing on single candidate mRNAs such as Arc/Arg 3.1, PSD-95, and MAP1B9–11 These studies have advanced the basic biology of FMRP function; there is an acute need for unbiased protein biomarkers for FXS to identify patient subgroups and treatment response. This lack of unbiased biomarkers has contributed to the failure of multiple clinical trials recently[12,13,14]. We evaluated the cross-tissue applicability of the candidates by testing the whole blood response of FXS model mice to treatment with pharmacological agents that ameliorate pathophysiology and their abundance in plasma from FXS individuals
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