Abstract
Abstract TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.
Original language | English (US) |
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Article number | 37221 |
Pages (from-to) | 1920-1928 |
Number of pages | 9 |
Journal | FEBS Letters |
Volume | 589 |
Issue number | 15 |
DOIs | |
State | Published - Jul 3 2015 |
Bibliographical note
Funding Information:This work was supported by National Basic Research Program of China (Grants 2012CB911003 and 2011CB911104 ) and National Natural Science Foundation of China (Grant 31270773 ).
Publisher Copyright:
© 2015 Federation of European Biochemical Societies.
Keywords
- C-terminal fragment of ∼35kDa
- Cytoplasmic inclusion
- RNA recognition motif
- Sequestration
- TAR DNA binding protein of 43kDa