Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43.
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| Abstract |
Intracellular aggregates of phosphorylated TDP-43 are a major component of ubiquitin-positive inclusions in the brains of patients with frontotemporal lobar degeneration and ALS and are considered a pathological hallmark. Here, to gain insight into the mechanism of intracellular TDP-43 accumulation, we examined the relationship between phosphorylation and aggregation of TDP-43. We found that expression of a hyperactive form of casein kinase 1 δ (CK1δ1-317, a C-terminally truncated form) promotes mislocalization and cytoplasmic accumulation of phosphorylated TDP-43 (ubiquitin- and p62-positive) in cultured neuroblastoma SH-SY5Y cells. Insoluble phosphorylated TDP-43 prepared from cells co-expressing TDP-43 and CK1δ1-317 functioned as seeds for TDP-43 aggregation in cultured cells, indicating that CK1δ1-317-induced aggregated TDP-43 has prion-like properties. A striking toxicity and alterations of TDP-43 were also observed in yeast expressing TDP-43 and CK1δ1-317. Therefore, abnormal activation of CK1δ causes phosphorylation of TDP-43, leading to the formation of cytoplasmic TDP-43 aggregates, which, in turn, may trigger neurodegeneration.
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| Authors | Takashi Nonaka, Genjiro Suzuki, Yoshinori Tanaka, Fuyuki Kametani, Shinobu Hirai, Haruo Okado, Tomoyuki Miyashita, Minoru Saitoe, Haruhiko Akiyama, Hisao Masai, Masato Hasegawa |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 11 Pg. 5473-5483 (Mar 11 2016) ISSN: 1083-351X [Electronic] United States |
| PMID | 26769969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. |
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