RNP2 of RNA Recognition Motif 1 Plays a Central Role in the Aberrant Modification of TDP-43

Shinnosuke Takagi, Yohei Iguchi, Masahisa Katsuno, Shinsuke Ishigaki, Kensuke Ikenaka, Yusuke Fujioka, Daiyu Honda, Jun ichi Niwa, Fumiaki Tanaka, Hirohisa Watanabe, Hiroaki Adachi, Gen Sobue

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Abstract

Phosphorylated and truncated TAR DNA-binding protein-43 (TDP-43) is a major component of ubiquitinated cytoplasmic inclusions in neuronal and glial cells of two TDP-43 proteinopathies, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Modifications of TDP-43 are thus considered to play an important role in the pathogenesis of TDP-43 proteinopathies. However, both the initial cause of these abnormal modifications and the TDP-43 region responsible for its aggregation remain uncertain. Here we report that the 32 kDa C-terminal fragment of TDP-43, which lacks the RNP2 motif of RNA binding motif 1 (RRM1), formed aggregates in cultured cells, and that similar phenotypes were obtained when the RNP2 motif was either deleted from or mutated in full-length TDP-43. These aggregations were ubiquitinated, phosphorylated and truncated, and sequestered the 25 kDa C-terminal TDP-43 fragment seen in the neurons of TDP-43 proteinopathy patients. In addition, incubation with RNase decreased the solubility of TDP-43 in cell lysates. These findings suggest that the RNP2 motif of RRM1 plays a substantial role in pathological TDP-43 modifications and that it is possible that disruption of RNA binding may underlie the process of TDP-43 aggregation.

Original languageEnglish
Article numbere66966
JournalPloS one
Volume8
Issue number6
DOIs
Publication statusPublished - 28-06-2013

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Takagi, S., Iguchi, Y., Katsuno, M., Ishigaki, S., Ikenaka, K., Fujioka, Y., Honda, D., Niwa, J. I., Tanaka, F., Watanabe, H., Adachi, H., & Sobue, G. (2013). RNP2 of RNA Recognition Motif 1 Plays a Central Role in the Aberrant Modification of TDP-43. PloS one, 8(6), [e66966]. https://doi.org/10.1371/journal.pone.0066966