Comprehensive analysis of TDP-43 target genes and binding proteins

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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.