TDP‐43 N‐terminal domain dimerisation or spatial separation by RNA binding decreases its propensity to aggregate
- 26 May 2023
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 597 (12), 1667-1676
- https://doi.org/10.1002/1873-3468.14635
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.Funding Information
- Japan Agency for Medical Research and Development (JP21ek0109503)
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