Protein homeostasis is impaired in fragile X syndrome

The Fragile X syndrome (FXS) is the most frequent form of monogenic intellectual disability and autism, caused by the absence of the fragile X mental retardation protein (FMRP). This leads to an increase in mRNA translation at synapses and, as a consequence, to deficits in synaptic architecture and plasticity. Here, we measured the rate of protein synthesis in fibroblasts derived from individuals with FXS as well as in Fmr1 KO embryonic fibroblasts (MEFs) and primary neurons. We show that levels of protein synthesis are disrupted in individuals and mice with FXS. However, translational rate is not increased in all patients, of note, a small proportion of FXS individuals and Fmr1 KO mice have measures in the normal range. Furthermore, we recently demonstrated that increase of protein synthesis is sustained by the excessive production of soluble amyloid precursor protein α (sAPPα), due to the impaired processing of the amyloid precursor protein (APP) during a critical developmental window in Fmr1 KO mice. Our laboratory has shown that modulation of APP processing using the cell permeable peptide TAT-Pro ADAM10709-729, is able to restore protein synthesis and rescue behavioral deficits in the FXS murine model (Pasciuto et al., 2015). Importantly, we now recapitulate those findings in fibroblasts and iPSCs derived from FXS individuals, showing a developmental-dependent impairment of APP processing in human cells. In addition, we found that the TAT-Pro ADAM10709-729 peptide might be a specific treatment to reduce sAPPα release and exaggerate protein synthesis rates in human cells.