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

Content Provider	SpringerLink
Author	Nagata, Eiichiro naka, Takashi Moriya, Yusuke Fujii, Natsuko Okada, Yoshiri Tsukamoto, Hideo Itoh, Johbu Okada, Chisa Satoh, Tadayuki Arai, Tetsuaki Hasegawa, Masato Takizawa, Shunya
Copyright Year	2015
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 (InsP$_{7}$) contains highly energetic pyrophosphate bonds. We previously reported that inositol hexakisphosphate kinase type 2 (InsP$_{6}$K2), which converts inositol hexakisphosphate (InsP$_{6}$) to InsP$_{7}$, mediates cell death in mammalian cells. Moreover, InsP$_{6}$K2 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 InsP$_{6}$K2 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 InsP$_{6}$K2. However, cells with only cytoplasmic TDP-43 aggregation survived because Akt activity increased. In the presence of both TDP-43 aggregation and activated InsP$_{6}$K2 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, InsP$_{6}$K2 could cause neuronal cell death in patients with FTLD-U or ALS. Moreover, InsP$_{6}$K2 plays an important role in a novel cell death pathway present in FTLD-U and ALS.
Starting Page	5377
Ending Page	5383
Page Count	7
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	53
Issue Number	8
e-ISSN	15591182
Language	English
Publisher	Springer US
Publisher Date	2015-10-06
Publisher Place	New York
Access Restriction	Subscribed
Subject Keyword	Inositol hexakisphosphate kinase 2 (InsP$_{6}$K2) Cell death TDP-43 Akt HSP90 Casein kinase 2 Amyotrophic lateral sclerosis (ALS) Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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