Smidak Roman, Sialana Fernando J, Kristofova Martina, Stojanovic Tamara, Rajcic Dragana, Malikovic Jovana, Feyissa Daniel D, Korz Volker, Hoeger Harald, Wackerlig Judit, Mechtcheriakova Diana, Lubec Gert
Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Vienna, Austria.
Front Aging Neurosci. 2017 Nov 23;9:384. doi: 10.3389/fnagi.2017.00384. eCollection 2017.
Fragile X mental retardation protein (FMRP) encoded by Fragile X mental retardation 1 () gene is a RNA-binding regulator of mRNA translation, transport and stability with multiple targets responsible for proper synaptic function. Epigenetic silencing of gene expression leads to the development of Fragile X syndrome (FXS) that is characterized by intellectual disability and other behavioral problems including autism. In the rat FXS model, the lack of FMRP caused a deficit in hippocampal-dependent memory. However, the hippocampal changes of FMRP in aging rats are not fully elucidated. The current study addresses the changes in FMRP levels in dentate gyrus (DG) from young (17 weeks) and aging (22 months) Sprague - Dawley rats. The aging animal group showed significant decline in spatial reference memory. Protein samples from five rats per each group were analyzed by quantitative proteomic analysis resulting in 153 significantly changed proteins. FMRP showed significant reduction in aging animals which was confirmed by immunoblotting and immunofluorescence microscopy. Furthermore, bioinformatic analysis of the differential protein dataset revealed several functionally related protein groups with individual interactions with FMRP. These include high representation of the RNA translation and processing machinery connected to FMRP and other RNA-binding regulators including CAPRIN1, the members of Pumilio (PUM) and CUG-BP, Elav-like (CELF) family, and YTH N(6)-methyladenosine RNA-binding proteins (YTHDF). The results of the current study point to the important role of FMRP and regulation of RNA processing in the rat DG and memory decline during the aging process.
脆性X智力低下1（FMR1）基因编码的脆性X智力低下蛋白（FMRP）是一种mRNA翻译、转运和稳定性的RNA结合调节因子，有多个靶点负责正常的突触功能。FMR1基因表达的表观遗传沉默导致脆性X综合征（FXS）的发生，其特征为智力残疾和包括自闭症在内的其他行为问题。在大鼠FXS模型中，FMRP的缺失导致海马依赖性记忆缺陷。然而，衰老大鼠海马中FMRP的变化尚未完全阐明。本研究探讨了年轻（17周）和衰老（22个月）的Sprague-Dawley大鼠齿状回（DG）中FMRP水平的变化。衰老动物组的空间参考记忆显著下降。通过定量蛋白质组分析对每组五只大鼠的蛋白质样本进行分析，结果显示有153种蛋白质发生了显著变化。免疫印迹和免疫荧光显微镜证实，衰老动物中FMRP显著减少。此外，对差异蛋白质数据集的生物信息学分析揭示了几个与FMRP有个体相互作用的功能相关蛋白质组。这些包括与FMRP相关的RNA翻译和加工机制的高表达，以及其他RNA结合调节因子，包括CAPRIN1、Pumilio（PUM）和CUG-BP、Elav样（CELF）家族成员，以及YTH N（6）-甲基腺苷RNA结合蛋白（YTHDF）。本研究结果表明FMRP以及RNA加工调节在大鼠DG和衰老过程中的记忆衰退中起重要作用。
