RNP2 of RNA recognition motif 1 plays a central role in the aberrant modification of TDP-43.
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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.
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| Authors | 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 |
| Journal | PloS one (PLoS One) Vol. 8 Issue 6 Pg. e66966 ( 2013) ISSN: 1932-6203 [Electronic] United States |
| PMID | 23840565 (Publication Type: Journal Article) |
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