Inositol hexakisphosphate kinase 2 promotes cell death of anterior horn cells in the spinal cord of patients with amyotr
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ORIGINAL ARTICLE
Inositol hexakisphosphate kinase 2 promotes cell death of anterior horn cells in the spinal cord of patients with amyotrophic lateral sclerosis Eiichiro Nagata1 · Natsuko Fujii1 · Saori Kohara1 · Chisa Okada2 · Tadayuki Satoh2 · Susumu Takekoshi3 · Masaki Takao4 · Ban Mihara5 · Shunya Takizawa1 Received: 13 January 2020 / Accepted: 26 July 2020 © Springer Nature B.V. 2020
Abstract We have previously reported that inositol hexakisphosphate kinase (InsP6K)2 mediates cell death. I nsP6K2 is abundantly expressed in anterior horn cells of the mammalian spinal cord. We investigated the role of InsP6K2 in spinal cords of patients with amyotrophic lateral sclerosis (ALS). Autopsy specimens of lumbar spinal cords from ten patients with sporadic ALS and five non-neurological disease patients (NNDPs) were obtained. We performed quantitative real-time PCR, immunostaining, and western blotting for I nsP6K1, InsP6K2, InsP6K3, protein kinase B (Akt), casein kinase 2 (CK2), and 90-kDa heat-shock protein (HSP90). In contrast to I nsP6K1 and I nsP6K3 mRNA expression, I nsP6K2 levels in anterior horn cells of the spinal cord were significantly increased in ALS patients compared to NNDPs. In ALS patients, I nsP6K2 translocated from the nucleus to the cytoplasm. However, we observed a decrease in HSP90, CK2, and Akt activity in ALS patients compared to NNDPs. A previous study reported that InsP6K2 activity is suppressed after binding to HSP90 and subsequent phosphorylation and degradation by CK2, thus decreasing InsP6K2 activity. However, InsP7, which is generated by InsP6K2, can compete with Akt for PH domain binding. Consequently, InsP7 can inhibit Akt phosphorylation. Our results suggest that InsP6K2 is activated in the spinal cord of patients with ALS and may play an important role in ALS by inducing cell death mechanisms via Akt, CK2, and HSP90 pathways. Keywords Inositol hexakisphosphate kinase 2 · Cell death · Amyotrophic lateral sclerosis · Spinal cord anterior horn cells · Akt depletion
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-05688-w) contains supplementary material, which is available to authorized users. * Eiichiro Nagata [email protected]‑tokai.ac.jp 1
Department of Neurology, Tokai University School of Medicine, 143 Shimo‑Kasuya, Isehara, Kanagawa 259‑1193, Japan
2
Support Center for Medical Research and Education, Tokai University, Isehara, Japan
3
Department of Clinical Pathology, Tokai University School of Medicine, Isehara, Japan
4
Department of Clinical Laboratory, National Center of Neurology and Psychiatry (NCNP), National Center Hospital, Tokyo, Japan
5
Department of Neurology, Mihara Memorial Hospital, Gunma, Japan
Inositol phosphates are indispensable cellular signaling molecules, and more than 20 inositol polyphosphates have been described in mammalian cells. However, several of these molecules have unknown physiological functions [1, 2]. Currently, inositol 1,4,5-trisphos
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