Binding of TDP-43 to the 3′UTR of Its Cognate mRNA Enhances Its Solubility

TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of a broad range of neurodegenerative diseases termed TDP-43 proteinopathies, which encompass a spectrum of diseases ranging from amyotrophic lateral sclerosis to frontotemporal dementia. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well-understood. Current hypotheses postulate that the TDP-43 aggregation process plays a major role in pathogenesis. We amplify that hypothesis and suggest that binding of cognate ligands to TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation. We expressed recombinant TDP-43 containing an N-terminal Venus yellow fluorescent protein tag in <i>Escherichia coli</i> and induced its aggregation by altering solvent salt concentrations and examined the extent to which various oligonucleotide molecules affect its aggregation <i>in vitro</i> using aggregation-induced turbidity assays. We show that vYFP-TDP-43 binding to its naturally occurring RNA target that comprises a sequence on the 3′UTR region of its mRNA improves its solubility, suggesting interplay among TDP-43 solubility, oligonucleotide binding, and TDP-43 autoregulation