Modeling Fragile X syndrome in neurogenesis: An unexpected phenotype and a novel tool for future therapies

Abstract

FMRP is an RNA-binding protein involved in synaptic translation. Its absence causes a form of intellectual disability, the Fragile X syndrome (FXS). Small neuroanatomical abnormalities, present both in human and mouse FMRP-deficient brains, suggest a subtle critical role of this protein in neurogenesis. Stable depletion of FMRP has been obtained in a mouse embryonic stem cell line Fmr1 (shFmr1 ES) that does not display morphological alterations, but an abnormal expression of a subset of genes mainly involved in neuronal differentiation and maturation. Inducing the differentiation of shFmr1 ES cells into the neuronal lineage results in an accelerated generation of neural progenitors and neurons during the first steps of neurogenesis. This transient phenotype is due to an elevated level of the Amyloid Precursor Protein (APP), whose mRNA is a target of FMRP. APP is processed by the BACE-1 enzyme, producing the β-amyloid (Aβ) peptide accelerating neurogenesis by activating the expression of Ascll. Inhibition of the BACE-1 enzyme rescues the phenotype of shFmr1 ES cells. Here we discuss the importance of the shFmr1 ES line not only to understand the physiopathology of FXS but also as a tool to screen biomolecules for new FXS therapies.

Keywords: Fragile X Syndrome; cell model for Fragile X syndrome; neurogenesis; therapy for Fragile X syndrome.

Figure 1.

A schema of the different steps of research we plan to carry out to define a treatment starting from the correction of the abnormal morphology of shFmr1 neural progenitors. First, starting from shFmr1 neural progenitors, a high throughput screening will be performed to identify those small molecules (of a selection of already approved drugs) that are able to revert the shFMR1 phenotype. These molecules will be tested in the Fmr1-null mice, the murine model of FXS, to define their ability to rescue some behavioral phenotypes of this mouse at different ages. In particular the impact of these molecules on social interaction and cognition deficits, and in hyperactivity of FXS mice will be evaluated. Molecules able to correct these phenotypes will be directly tested on FXS patients in Phase II clinical trials.