Identification of RNA bound to the TDP-43 ribonucleoprotein complex in the adult mouse brain
Identification of RNA bound to the TDP-43 ribonucleoprotein complex in the adult mouse brain
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DOI：
10.3109/21678421.2012.734520
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发表时间：
2013-05-01
影响因子：
2.8
通讯作者：
Wallace, Robyn H.
中科院分区：
文献类型：
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作者：
Narayanan, Ramesh K.;Mangelsdorf, Marie;Wallace, Robyn H.
含有 TDP-43 的细胞质内含物是多种神经退行性疾病的病理标志，包括肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆。 TDP-43 是一种 RNA 结合蛋白，通过控制 RNA 转录、剪接和运输参与基因调控。然而，TDP-43在神经系统中的功能很大程度上未知，其在ALS发病机制中的作用也不清楚。本研究的目的是鉴定中枢神经系统中受 TDP-43 调节的基因。使用抗 TDP-43 抗体进行 RNA 免疫沉淀，然后进行微阵列分析（RIP 芯片），用于分离和鉴定与小鼠大脑中的 TDP-43 蛋白结合的 RNA。这项分析产生了 1839 个潜在 TDP-43 基因靶标的列表，其中许多与之前的研究重叠，其功能包括 RNA 加工和突触功能。免疫组织化学表明，TDP-43 蛋白存在于小鼠神经肌肉接头轴突末端的突触前膜上。总之，TDP-43 与编码突触功能相关基因的 RNA 结合的发现，以及 TDP-43 蛋白在轴突末端的定位，表明 TDP-43 在将突触 mRNA 转运到远端过程中发挥着作用。
Cytoplasmic inclusions containing TDP-43 are a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP-43 is an RNA binding protein involved in gene regulation through control of RNA transcription, splicing and transport. However, the function of TDP-43 in the nervous system is largely unknown and its role in the pathogenesis of ALS is unclear. The aim of this study was to identify genes in the central nervous system that are regulated by TDP-43. RNA-immunoprecipitation with anti-TDP-43 antibody, followed by microarray analysis (RIP-chip), was used to isolate and identify RNA bound to TDP-43 protein from mouse brain. This analysis produced a list of 1839 potential TDP-43 gene targets, many of which overlap with previous studies and whose functions include RNA processing and synaptic function. Immunohistochemistry demonstrated that the TDP-43 protein could be found at the presynaptic membrane of axon terminals in the neuromuscular junction in mice. In conclusion, the finding that TDP-43 binds to RNA that codes for genes related to synaptic function, together with the localization of TDP-43 protein at axon terminals, suggests a role for TDP-43 in the transport of synaptic mRNAs into distal processes.