Journal
FEBS LETTERS
Volume 597, Issue 12, Pages 1667-1676Publisher
WILEY
DOI: 10.1002/1873-3468.14635
Keywords
aggregation; ALS; dimerisation; FTLD; N-terminal domain interaction; RNA binding; solubility; spatial organisation; TDP-43; UG-repeats
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This study reveals two mechanisms for modulating the solubility of TDP-43 through RNA binding: N-terminal domain dimerization and spatial separation of TDP-43 molecules. These findings provide new insights into the regulation of TDP-43 solubility.
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.
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