Mechanism of the nerve cell death accompanied with tau protein phosphorylation in tauopathy

tau蛋白病中伴随tau蛋白磷酸化的神经细胞死亡机制

• 批准号: 14570922
• 负责人: TANAKA Toshihisa
• 金额: $ 1.92万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570922/
• 关键词: Alzheimer disease; tau Protein; neuronal cell death; tauopathy; double stranded RNA; neurofibilliary tangles; 神経細胞死; アポトーシス; リボトキシックストレス

Neurofibrillary tangles (NFTs) are neuropathological hallmarks of Alzheimer disease (AD) and abnormally hyperphosphorylated tau is the major. protein component of NFTs. Accumulation of hyperphosphorylated tau protein is also observed in other neurodegenerative diseases including subacute sclerosing panencephaltis (SSPE), and SSPE is caused by infection with measles RNA virus. Polyinosinic-polycytidylic acid (Poly(I ; C)), synthetic double stranded RNA (dsRNA), has been often used to make virus-infected cell models. We previously reported that tau protein phosphorylation in cells, was induced by dsRNA through TLR3 activation.In this study effects of dsRNA was examined on microtubule-polymerization by tau and self-polymerization of tau, because tau is a negative-charged protein that has a similar character as gulucosaminoglycans including heparin. In binding assay poly(I ; C) was bound with *combinant GST-Staufen Δ tub which was a typical dsRNA binding protein lacking tubulin-binding domain, or tau protein, but not with actin or tubulin. Next, the polymerization of the microtubule was examined in the presence and absence of 0.2mg/ml of Poly(I ; C), and it was found that confirmed that the polymerization of the microtubule decreased remarkably in the presence of Poly(I ; C). When tau (1.6mg/mi) and Poly(LC) (0.8mg/ml) were mixed and incubated for 48 hours at 37℃, the electron microscopic study showed there were straight fibers (20-3Onm diameter).It was suggested that dsRNA outside of neuronal cells induced tau protein phosphorylation through TLR activation and that dsRNA inside of neuronal cells disturbed the microtubule polymerization and promoted filament formations of tau protein.Polyinosinic-polycytidylic acid (pI-pC), synthetic

神经原纤维缠结（nft）是阿尔茨海默病（AD）的神经病理学标志，异常过度磷酸化的tau是主要的。nft的蛋白质成分。在其他神经退行性疾病中也观察到高磷酸化tau蛋白的积累，包括亚急性硬化性全脑炎（SSPE）， SSPE是由麻疹RNA病毒感染引起的。多肌苷-多胞苷酸（Poly(I； C)）是合成的双链RNA (dsRNA)，常用于制作病毒感染的细胞模型。我们之前报道过细胞中的tau蛋白磷酸化是由dsRNA通过TLR3激活诱导的。在这项研究中，dsRNA对tau微管聚合和tau自聚合的影响进行了研究，因为tau是一种带负电荷的蛋白质，与包括肝素在内的古葡聚糖具有相似的特性。在结合实验中，poly（I； C）与*组合GST-Staufen Δ tub结合，这是一种典型的缺乏微管蛋白结合结构域的dsRNA结合蛋白，或tau蛋白，但不与肌动蛋白或微管蛋白结合。接下来，在0.2mg/ml Poly（I； C）存在和不存在的情况下检测微管的聚合，发现证实在Poly（I； C）存在下微管的聚合明显降低。将tau （1.6mg/mi）和Poly(LC) （0.8mg/ml）混合，在37℃下孵育48小时，电镜观察显示有直纤维（直径20-3Onm）。提示神经元细胞外的dsRNA通过TLR激活诱导tau蛋白磷酸化，神经元细胞内的dsRNA干扰微管聚合，促进tau蛋白的细丝形成。聚肌苷-多胞苷酸（pI-pC）的合成

项目成果

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Pei, J.J. 等人：“蛋白激酶 B 在阿尔茨海默病神经原纤维病理学中的作用”Acta Neuropathol (Berl)。

田中稔久 他: "免疫療法の開発と問題点"臨床精神医学. 31. 1177-1180 (2002)

Toshihisa Tanaka 等人：“免疫疗法的发展和问题”临床精神病学 31. 1177-1180 (2002)

田中稔久, 武田雅俊: "タウのリン酸化とリン酸化の調節機構"日本臨床・増刊号「痴呆症学I」. 61. 66-72 (2003)

Toshihisa Tanaka、Masatoshi Takeda：“Tau 磷酸化和磷酸化的调节机制”日本临床特刊“痴呆研究 I”61. 66-72 (2003)。

田中稔久, 武田雅俊: "タウのリン酸化とリン酸化の調節機構"日本臨床・増刊号「痴呆症学I」. 61・9. 66-72 (2003)

田中敏久、武田正俊：“Tau 磷酸化和磷酸化的调节机制”日本临床特刊“痴呆研究 I”61・9（2003 年）。

Tanaka, T., et al.: "Study on the interaction of inhibitor of apoptosis protein with tau protein and the neurodegeneration"Annual reportsof neuropsychiatry (Japanese). 35. 63-73 (2003)

Tanaka, T.等人：“凋亡蛋白抑制剂与tau蛋白相互作用及神经变性的研究”神经精神病学年度报告（日文）。