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.脆性X综合征（Fragile X syndrome, FXS）患者体内FMR1基因呈沉默状态，而前突变携带者体内该基因的表达水平可升高2~8倍。此类人群可能罹患脆性X相关震颤共济失调综合征（Fragile X-associated Tremor Ataxia Syndrome, FXTAS），这是一种以共济失调与帕金森综合征为典型特征的迟发性神经退行性疾病。此外，携带前突变的个体在青年阶段可能出现一系列神经及行为异常病症。研究人员已在这类患者以及FXTAS小鼠模型中均检测到记忆障碍问题。尽管FMR1基因的表达需要精细调控且该调控机制具有重要意义，但截至目前，学界对FMR1 mRNA的代谢过程仍知之甚少。本研究鉴定出3种可特异性靶向FMR1基因3'非翻译区（3'UTR）的微小RNA（microRNA），它们能够在全脑范围内调控该基因的表达，尤其在突触部位发挥调控作用。miR-221在年轻FXTAS小鼠的脑组织及突触体制备物中表达水平降低，提示此类小鼠的突触部位转录本普遍存在调控异常。通过转录组分析，本研究证实与学习记忆、自闭行为、帕金森病及神经退行性变相关的基因表达水平存在显著紊乱。有趣的是，其中许多异常调控的mRNA，正是那些在突触部位调控FMR1表达的同一类微小RNA的靶标。本实验设置敲入（Knock-In）与野生型（Wild Type）两组，每组均设3次生物学重复。