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

Abstract

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 has been suggested to ameliorate TDP‐43 aggregation. However, the relationship between these factors and the solubility of TDP‐43 is largely unknown. Therefore, we developed new oligonucleotides that 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 the spatial separation of two TDP‐43 molecules. This study provides new molecular insights into the regulation of TDP‐43 solubility.