Comprehensive analysis of TDP-43 target genes and binding proteins

TAR DNA结合蛋白-43（TDP-43）是一种进化保守的核蛋白，通过与多种靶RNA和相互作用蛋白形成多分子复合物来调节基因表达。异常磷酸化、泛素化和聚集的TDP-43蛋白构成肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）患者脑中神经元和神经胶质细胞胞质和核内含物的主要成分，建立了一种新的临床实体，称为TDP-43蛋白病。尽管越来越多的证据表明ALS和FTLD的神经退行性过程可归因于TDP-43的毒性功能获得或细胞功能丧失，但确切的分子机制仍不清楚。系统生物学的最新进展使我们能够利用生物信息学的途径分析工具，从基因组、转录组和蛋白质组的大规模数据中提取全球分子网络，并赋予其全面的知识基础。本研究旨在表征TDP-43靶RNA和相互作用蛋白质的全面分子网络，这些蛋白质最近通过下一代测序仪和质谱分析进行了深度测序。我们的研究结果提出了系统生物学观点，即TDP-43作为RNA依赖的基因转录和翻译调节的分子协调者，对执行不同的神经元功能至关重要，TDP-43介导的分子协调的破坏诱导ALS和FTLD的神经变性。

TAR DNA-binding protein-43 (TDP-43) is an evolutionarily conservednuclear protein that regulates gene expression by forming a multimolecular complex with a wide varietyof target RNAs and interacting proteins. Abnormally phosphorylated, ubiquitinated, and aggregatedTDP-43 proteins constitute a principal component of neuronal and glial cytoplasmic and nuclearinclusions in the brains of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), establishing a novel clinical entity designated TDP-43 proteinopathy. Althoughincreasing evidence suggests that the neurodegenerative process underlying ALS and FTLD isattributable to a toxic gain of function or a loss of cellular function of TDP-43, the precise molecularmechanisms remain largely unknown. Recent advances in systems biology enable us to characterize theglobal molecular network extracted from large-scale data of the genome, transcriptome, and proteomewith the pathway analysis tools of bioiformatics endowed with a comprehensive knowledge base. Thepresent study was conducted to characterize the comprehensive molecular network of TDP-43 targetRNAs and interacting proteins, recently identified by deep sequencing with next-generation sequencersand mass spectrometric analysis. Our results propose the systems biological view that TDP-43 serves as a molecular coordinator of the RNA-dependent regulation of gene transcription and translation pivotal for performing diverse neuronal functions and that the disruption of TDP-43-mediated molecularcoordination induces neurodegeneration in ALS and FTLD.