A seeding reaction recapitulates intracellular formation of sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions

Yoshiaki Furukawa, Kumi Kaneko, Shoji Watanabe, Koji Yamanaka, Nobuyuki Nukina

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

The transactivation response element (TAR) DNA-binding protein-43 (TDP-43) is a nuclear protein that normally regulates transcription and splicing. Abnormal accumulation of insoluble inclusions containing TDP-43 has been recently reported in the affected tissues of amyotrophic lateral sclerosis (ALS) patients. Here, we show that intracellular aggregation of TDP-43 can be triggered by transduction of fibrillar aggregates prepared from in vitro functional TDP-43. Sarkosyl is found to be incapable of solubilizing those intracellularly seeded aggregates of TDP-43, which is consistent with the observation that TDP-43 inclusions in ALS patients are sarkosyl-insoluble. In addition, intracellular seeding in our cell models reproduces ubiquitination of TDP-43 aggregates, which is another prominent feature of TDP-43 inclusions in ALS patients. Although it has been so far difficult to initiate disease-associated changes of TDP-43 using cultured cell models, we propose that a seeding reaction is a key to construct a model to monitor TDP-43 pathologies.

Original languageEnglish
Pages (from-to)18664-18672
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number21
DOIs
Publication statusPublished - 2011 May 27

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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