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Molecular Network Analysis of Target RNAs and Interacting Proteins of TDP-43, a Causative Gene for the Neurodegenerative Diseases ALS/FTLD
Abstract
TAR DNA-binding protein-43 (TDP-43) is an evolutionarily conserved nuclear protein that regulates gene expression by forming a multimolecular complex with a wide variety of target RNAs and interacting proteins. Abnormally phosphorylated, ubiquitinated, and aggregated TDP-43 proteins constitute a principal component of neuronal and glial cytoplasmic and nuclear inclusions in the brains of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), establishing a novel clinical entity designated TDP-43 proteinopathy. Although increasing evidence suggests that the neurodegenerative process underlying ALS and FTLD is attributable to a toxic gain of function or a loss of cellular function of TDP-43, the precise molecular mechanisms remain largely unknown. Recent advances in systems biology enable us to characterize the global molecular network extracted from large-scale data of the genome, transcriptome, and proteome with the pathway analysis tools of bioinformatics endowed with a comprehensive knowledge base. The present study was conducted to characterize the comprehensive molecular network of TDP-43 target RNAs and interacting proteins, recently identified by deep sequencing with next-generation sequencers and mass spectrometric analysis. The 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 molecular coordination induces neurodegeneration in ALS and FTLD.
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