The 3 UTR of FMR1 mRNA is a target of miR-101, miR-129-5p and miR-221: implications for the molecular pathology of FXTAS at the synapse

While FMR1 is silenced in Fragile X syndrome (FXS) patients carrying the full mutation, its expression is elevated (28 fold) in premutated individuals. These people may develop the Fragile X-associated Tremor/Ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by ataxia and parkinsonism. In addition, people carrying the premutation can be affected by a set of neurological and behavioral disorders during young age. Problems of memory have been detected in these patients as well as in the mouse models for FXTAS. To date little is known concerning the metabolism of FMR1 mRNA, notwithstanding the importance of the finely tuned regulation of the expression of this gene. In the present study, we identified three microRNAs that specifically target the 3 UTR of FMR1 and can modulate its expression throughout the brain particularly at the synapse where their expression is very high. The expression level of miR-221 is reduced in synaptosomal preparations of young FXTAS mice suggesting a general deregulation of transcripts located at the synapse of these mice. By transcriptome analysis, we show here a robust deregulation of the expression levels of genes involved in learning, memory and autistic behavior, Parkinson disease and neurodegeneration. These findings suggest the presence of a synaptopathy in these animals. Interestingly, many of those deregulated mRNAs are target of the same microRNAs that modulate the expression of FMR1 at the synapse.