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

Mei Xia Che, Ya Jun Jiang, Yuan Yuan Xie, Lei Lei Jiang, Hong Yu Hu

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2344-2353
Number of pages10
JournalFASEB Journal
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2011

Keywords

  • Amyotrophic lateral sclerosis
  • Delocalization
  • Pre-mRNA splicing
  • Seeding
  • TDP-35

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