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Molecular Neurobiology

, Volume 53, Issue 8, pp 5377–5383 | Cite as

Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

  • Eiichiro Nagata
  • Takashi Nonaka
  • Yusuke Moriya
  • Natsuko Fujii
  • Yoshinori Okada
  • Hideo Tsukamoto
  • Johbu Itoh
  • Chisa Okada
  • Tadayuki Satoh
  • Tetsuaki Arai
  • Masato Hasegawa
  • Shunya Takizawa
Article

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.

Keywords

Inositol hexakisphosphate kinase 2 (InsP6K2) Cell death TDP-43 Akt HSP90 Casein kinase 2 Amyotrophic lateral sclerosis (ALS) Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) 

Notes

Conflict of Interests

The authors declare that they have no conflict of interests.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Eiichiro Nagata
    • 1
    • 5
  • Takashi Nonaka
    • 2
  • Yusuke Moriya
    • 1
  • Natsuko Fujii
    • 1
  • Yoshinori Okada
    • 3
  • Hideo Tsukamoto
    • 3
  • Johbu Itoh
    • 3
  • Chisa Okada
    • 3
  • Tadayuki Satoh
    • 3
  • Tetsuaki Arai
    • 4
  • Masato Hasegawa
    • 2
  • Shunya Takizawa
    • 1
  1. 1.Department of NeurologyTokai University School of MedicineIseharaJapan
  2. 2.Department of Neuropathology and Cell BiologyTokyo Metropolitan Institute of Medical ScienceTokyoJapan
  3. 3.Support Center for Medical Research and EducationTokai UniversityIseharaJapan
  4. 4.Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  5. 5.IseharaJapan

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