脆性X智力低下基因（FMR1）编码蛋白FMRP具有调节脑发育和神经元突触可塑性作用。除了导致脆性X综合征外，目前已证实FMR1基因前突变携带者可产生一种退行性疾病- - 脆性X 相关震颤和(或)共济失调综合征（FXTAS），其中RNA结合蛋白DGCR8所参与的miRNA加工途径可能在FXTAS中发挥重要作用，但分子机制不明。在前期工作中我们首次发现一例FXTAS患者只有FMR1基因编码区错义突变（P626L），并证实该突变在转录后水平上负性调控DGCR8的表达，提示该突变通过与FMR1基因前突变不同的调控途径参与FXTAS发生。本项目将进一步研究正常及突变FMRP对DGCR8的表达调控途径，并且通过构建突变转基因小鼠，分析该突变通过DGCR8改变miRNAs及其下游靶基因的表达情况，还将研究转基因小鼠脑组织形态结构和运动协调性变化，以期揭示FMR1基因突变在神经元退行性病变中的分子机制。

Fragile X mental retardation gene (FMR1，encoding fragile X mental retardation protein FMRP) plays an important role in brain development and synaptic plasticity. FMR1 is associated with neurodevelopmental and neurodegenerative disorders. It has been demonstrated that FMR1 pre-mutation can lead to fragile X-associated tremor and (or) ataxia syndrome (FXTAS), in which DGCR8-mediated microRNA pathway is involved. However, the molecular pathogenic mechanism underlying the FMR1 mutation in FXTAS is still poorly known. Our previous study identified a FMR1 missense mutation (P626L) in a FXTAS patient. Further analysis showed that the P626L mutation could downregulate DGCR8 expression at posttranscriptional level, suggesting a pathogenic effect of this mutation in FXTAS. The project will further investigate the role of wild-type and mutant FMRP in regulating the DGCR8-mediated microRNA pathway in vitro. We will construct a transgenic mouse containing this mutation and analyze the regulatory role of the P626L mutation in the expressions of microRNAs and their target genes by affecting DGCR8 expression at molecular and cellular levels. We will also analyze the changes in brain morphology and behavior in the transgenic mice. This study will reveal the molecular mechanisms underlying the neurodegenerative disease resulted from the FMR1 mutation.