Aggregation of TDP-43 fragments triggers cellular aberrant function: implication in neurodegeneration
© Che et al; licensee BioMed Central Ltd. 2012
Published: 7 February 2012
TAR DNA binding protein of 43 kDa (TDP-43) is a nuclear factor functioning in RNA processing. It was also reported that TDP-43 aggregates are deposited in motor neurons implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin (FTLD-U). To understand the mechanism underlying the inclusion body formation and possible functional alteration of TDP-43, we studied TDP-43 and its fragments and their effects on RNA processing in vitro and in cell models. We have identified a hydrophobic sequence in the C-terminus that is critical for the TDP-43 aggregation and inclusion formation. The synthetic peptide with this sequence forms an α-helical structure in solution but easily transforms into β-sheet structure. The inclusions formed by the C-terminal 35-kDa fragment (TDP-35) can recruit full-length TDP-43 to cytoplasmic deposition from functionally nuclear localization. TDP-35, rather than TDP-43 and the C-terminal 25-kDa fragment, is prone to aggregation in vitro, and it can further serve as a seed to facilitate aggregation of full-length TDP-43. This suggests that fragmentation of TDP-43 leads to cellular redistribution, inclusion body formation, and altered RNA processing, which are implicated in the molecular pathogenesis of ALS and FTLD.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.