TDP-43 N-terminal domain dimerisation or spatial separation by RNA binding decreases its propensity to aggregate.

Aggregation of the 43 kDa TAR DNA-binding protein (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RNA binding and TDP-43 N-terminal domain dimerisation have been suggested to ameliorate TDP-43 aggregation. However, the relationship between these factors and solubility of TDP-43 is largely unknown. Therefore, we developed new oligonucleotides which can recruit two TDP-43 molecules and interfere with their intermolecular interactions via spatial separation. Using these oligonucleotides and TDP-43-preferable UG-repeats, we uncovered two distinct mechanisms for modulating TDP-43 solubility by RNA binding: one is N-terminal domain dimerisation and the other is spatial separation of two TDP-43 molecules. This study provides new molecular insights into the regulation of TDP-43 solubility.