title: Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43.
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.
authors.affiliation: From the Dementia Research Project and. Electronic address: nonaka-tk@igakuken.or.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.affiliation: From the Dementia Research Project and.
authors.forename: Genjiro
authors.initials: G
authors.lastname: Suzuki
authors.affiliation: From the Dementia Research Project and.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: From the Dementia Research Project and.
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Kametani
authors.affiliation: Departments of Brain Development and Neural Regeneration.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Departments of Brain Development and Neural Regeneration.
authors.forename: Haruo
authors.initials: H
authors.lastname: Okado
authors.affiliation: Sensory and Motor Systems, and.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Sensory and Motor Systems, and.
authors.forename: Minoru
authors.initials: M
authors.lastname: Saitoe
authors.affiliation: From the Dementia Research Project and.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Genome Medicine, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Masai
authors.affiliation: From the Dementia Research Project and.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D000595:Amino Acid Sequence; D048148:Casein Kinase Idelta / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011328:Prions / Q000032:analysis / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D021381:Protein Transport
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions; D066329:Protein Aggregates; D048148:Casein Kinase Idelta
keywords: ALS (Lou Gehrig disease); TAR DNA-binding protein of 43 kDa (TDP-43); casein kinase 1δ; frontotemporal lobar degeneration (FTLD); phosphorylation; protein aggregation; protein kinase