Aggregation of the 35‐kDa fragment of TDP‐43 causes formation of cytoplasmic inclusions and alteration of RNA processing

Abstract

ABSTRACT TAR DNA binding protein of 43 kDa (TDP‐43) is a nuclear factor functioning in RNA processing. It is also a major deposited protein in 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, we studied some TDP‐43 fragments and their effects on RNA processing in cell models. The results show that the 35‐kDa fragment of TDP‐43 (namely TDP‐35, residues 90‐414), but not TDP‐25A (184–414), is capable of forming cytoplasmic inclusion bodies and altering pre‐mRNA splicing. The inclusions formed by TDP‐35 can also recruit full‐length TDP‐43 to cytoplasmic deposition from functionally nuclear localization. The in vitro studies demonstrate that TDP‐35, rather than TDP‐43 and TDP‐25A, is prone to aggregation, and it further serves 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.—Che, M.‐X., Jiang, Y.‐J., Xie, Y.‐Y., Jiang, L.‐L., Hu, H.‐Y. Aggregation of the 35‐kDa fragment of TDP‐43 causes formation of cytoplasmic inclusions and alteration of RNA processing. FASEB J. 25, 2344–2353 (2011). www.fasebj.org