The 3’UTR of FMR1 mRNA is a target of miR101, miR129-5p and miR-221: implications for the molecular pathology of FXTAS at the synapse

While FMR1 is silenced in Fragile X syndrome (FXS), its expression is elevated (2-8 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 behavioural disorders during young age. Problems of memory have been detected in these patients as well in the mice model 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 and, in particular, at the synaptic level. The expression level of miR-221 is reduced in brain and 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. Interestingly, many of those deregulated mRNAs are target of the same miRNAs that modulate the expression of FMR1 at the synapse. Knock-In versus Wild Type, 3 replicates.