title: Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation.
abstract: TAR DNA-binding protein 43 (TDP-43) has been identified as a major component of ubiquitin-positive inclusions in the brains and spinal cords of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) or amyotrophic lateral sclerosis (ALS). The phosphorylated C-terminal fragment of TDP-43 forms aggregates in the neuronal cytoplasm, possibly resulting in neuronal cell death in patients with FTLD-U or ALS. The inositol pyrophosphate known as diphosphoinositol pentakisphosphate (InsP7) contains highly energetic pyrophosphate bonds. We previously reported that inositol hexakisphosphate kinase type 2 (InsP6K2), which converts inositol hexakisphosphate (InsP6) to InsP7, mediates cell death in mammalian cells. Moreover, InsP6K2 is translocated from the nucleus to the cytosol during apoptosis. In this study, we verified that phosphorylated TDP-43 co-localized and co-bound with InsP6K2 in the cytoplasm of anterior horn cells of the spinal cord. Furthermore, we verified that cell death was augmented in the presence of cytoplasmic TDP-43 aggregations and activated InsP6K2. However, cells with only cytoplasmic TDP-43 aggregation survived because Akt activity increased. In the presence of both TDP-43 aggregation and activated InsP6K2 in the cytoplasm of cells, the expression levels of HSP90 and casein kinase 2 decreased, as the activity of Akt decreased. These conditions may promote cell death. Thus, InsP6K2 could cause neuronal cell death in patients with FTLD-U or ALS. Moreover, InsP6K2 plays an important role in a novel cell death pathway present in FTLD-U and ALS.
authors.affiliation: Department of Neurology, Tokai University School of Medicine, Isehara, Japan. enagata@is.icc.u-tokai.ac.jp.|, 143 Shimo-Kasuya, Isehara, Kanagawa, 259-1193, Japan. enagata@is.icc.u-tokai.ac.jp.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nagata
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.affiliation: Department of Neurology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Department of Neurology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Johbu
authors.initials: J
authors.lastname: Itoh
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Okada
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Neurology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Takizawa
mesh_terms: D047390:Casein Kinase II / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D066329:Protein Aggregates; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D066329:Protein Aggregates; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase
keywords: Akt; Amyotrophic lateral sclerosis (ALS); Casein kinase 2; Cell death; Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U); HSP90; Inositol hexakisphosphate kinase 2 (InsP6K2); TDP-43