Of Men and Mice: Modeling the Fragile X Syndrome

Abstract

The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research.

Rate of protein synthesis is reduced in peripheral blood mononuclear cells (PBMCs) from Fragile X individuals

“…Although not statistically signi cant, the same group recently reported a similar effect using dexmedetomidine as a sedating agent instead of propofol; thereby strongly suggesting that the observed decreased in the rate of protein synthesis is not caused by sedating agents [23]. These reports shed new light on translational regulation in FXS and highlights limitations of the Fmr1 KO mouse model to fully replicate FXS phenotype and the necessity to further study FX subjects in order to get a better understanding of the human physiopathology [24]. Such task represents a substantial challenge due to the inaccessibility and invasive nature of neuronal tissue, thus emphasizing the need to use a less invasive model.…”

The m6A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

“…The absence of FMRP leads to the FXS, which is a severe inherited neuronal disorder that currently lacks efficient therapeutic treatment. The phenotype of the patients suffering from FXS is often complex, accompanied by an increase in autism spectrum disorder specific traits and other features like delayed motor development, hyperactivity, aggression and epileptic seizures (reviewed in (Dahlhaus, 2018;Garber et al, 2008;Hagerman et al, 2014;Hagerman et al, 2002;Kidd et al, 2014;Maurin et al, 2014;Santoro et al, 2012;Schaefer et al, 2015;Utari et al, 2010)). These abnormalities result from defects in neuronal development and maturation.…”

Application of Human‐Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders

“…However, there are no reports on behavioral deficits for mice with full-mutation (200-350 repeats) (Hunsaker et al, 2010;Ludwig et al, 2014). In addition, neither DNA methylation nor FMR1 inactivation is achieved even in mice with full expansion (350 repeats) (Entezam et al, 2007;Alam et al, 2010;Dahlhaus, 2018). Therefore, the use of human neuronal models will be advantageous to the Figure 1 Overall workflow of hiPSC to study synaptic dysfunction in neurodevelopmental disorders.…”