Inositol hexakisphosphate kinase 2 promotes cell death of anterior horn cells in the spinal cord of patients with amyotrophic lateral sclerosis
Inositol hexakisphosphate kinase 2 promotes cell death of anterior horn cells in the spinal cord of patients with amyotrophic lateral sclerosis
复制标题
肌醇六磷酸激酶2促进肌萎缩侧索硬化症患者脊髓前角细胞死亡
DOI：
10.1007/s11033-020-05688-w
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发表时间：
2020
影响因子：
2.8
通讯作者：
Takizawa Shunya
中科院分区：
文献类型：
--
作者：
Nagata Eiichiro;Fujii Natsuko;Kohara Saori;Okada Chisa;Satoh Tadayuki;Takekoshi Susumu;Takao Masaki;Mihara Ban;Takizawa Shunya
我们以前曾报道，肌醇六磷酸激酶（InsP 6 K）2介导的细胞死亡。InsP 6 K2在哺乳动物脊髓前角细胞中大量表达。我们研究了InsP 6 K2在肌萎缩侧索硬化（ALS）患者脊髓中的作用。从10例散发性ALS患者和5例非神经系统疾病患者（NNDPs）的腰椎脊髓尸检标本。我们对InsP 6 K1、InsP 6 K2、InsP 6 K3、蛋白激酶B（Akt）、酪蛋白激酶2（CK 2）和90-kDa热休克蛋白（HSP 90）进行了定量实时PCR、免疫染色和蛋白质印迹。与InsP 6 K1和InsP 6 K3 mRNA表达相反，与NNDPs相比，ALS患者脊髓前角细胞中的InsP 6 K2水平显著增加。在ALS患者中，InsP 6 K2从细胞核易位到细胞质。然而，我们观察到ALS患者的HSP 90，CK 2和Akt活性与NNDPs相比有所下降。先前的研究报道，InsP 6 K2活性在与HSP 90结合并随后被CK 2磷酸化和降解后被抑制，从而降低InsP 6 K2活性。然而，由InsP 6 K2产生的InsP 7可以与Akt竞争PH结构域结合。因此，InsP 7可以抑制Akt的磷酸化。我们的研究结果表明，InsP 6 K2在ALS患者的脊髓中被激活，并可能通过Akt，CK 2和HSP 90途径诱导细胞死亡机制在ALS中发挥重要作用。
We have previously reported that inositol hexakisphosphate kinase (InsP6K)2 mediates cell death. InsP6K2 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 InsP6K1, InsP6K2, InsP6K3, protein kinase B (Akt), casein kinase 2 (CK2), and 90-kDa heat-shock protein (HSP90). In contrast to InsP6K1 and InsP6K3 mRNA expression, InsP6K2 levels in anterior horn cells of the spinal cord were significantly increased in ALS patients compared to NNDPs. In ALS patients, InsP6K2 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, InsP7can 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.