TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. 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. We postulate that the aggregation process plays a major role in pathogenesis, and we hypothesize that oligonucleotide ligands of TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation of this aggregation-prone protein. Using recombinant TDP-43 we were able to examine the extent to which various oligonucleotide molecules affects its aggregation in vitro. We have found that certain natural sequence and de novo designed oligonucleotides bind TDP-43 and prevent its natural tendency to aggregate. The clinical and therapeutic implications of these findings are discussed.

TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. 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. We postulate that the aggregation process plays a major role in pathogenesis, and we hypothesize that oligonucleotide ligands of TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation of this aggregation-prone protein. Using recombinant TDP-43 we were able to examine the extent to which various oligonucleotide molecules affects its aggregation in vitro. We have found that certain natural sequence and de novo designed oligonucleotides bind TDP-43 and prevent its natural tendency to aggregate. The clinical and therapeutic implications of these findings are discussed.