Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L Tau but not wild-type Tau
Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L Tau but not wild-type Tau
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DOI：
10.1074/jbc.m611876200
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发表时间：
2007-07-13
影响因子：
4.8
通讯作者：
Tamaoka, Akira
中科院分区：
文献类型：
--
作者：
Aoyagi, Hirofumi;Hasegawa, Masato;Tamaoka, Akira
17号染色体相关的额颞叶痴呆和帕金森病（FTDP-17）是由tau基因突变引起的常染色体显性遗传神经退行性疾病，其神经病理学特征是神经元内丝状包裹体过度磷酸化的tau蛋白。生化和免疫细胞化学分析表明，只有突变型tau沉积在P301L错义突变患者中，而野生型和突变型tau沉积在R406W突变患者中(Miyasaka， T., Morishima-Kawashima， M., Ravid， R., Kamphorst， W., Nagashima， K., and Ihara， Y. (2001) J. Neuropathol。与Miyasaka， T., Morishima-Kawashima， M., Ravid， R., Heutink， P., van Swieten， J. C., Nagashima， K.和Ihara， Y. (2001) Am。[j] .中华疾病杂志，2004,18(3):379 -379。在这里，我们测试了单体tau的成核能力和从细菌表达的人tau中获得的纤维原核的播种能力。P301L突变体tau的成核能力高于野生型tau，而R406W突变体tau的成核能力与野生型tau相似。令人惊讶的是，由P301L突变型tau组成的纤原核增强了P301L突变型tau在细丝中的组装，但并未促进野生型tau形成细丝。相反，由R406W突变体tau组成的细胞核支持野生型tau和R406W突变体tau形成细丝，由野生型tau组成的细胞核也是如此。蛋白水解分析表明，P301L突变体tau组成的细胞核的亚结构与野生型或R406W突变体tau组成的细胞核不同。因此，纤维原核和单体蛋白之间的相互作用似乎在tau丝组装机制中起重要作用。
Frontotemporal dementia and parkinsonism linked to chromosome 17 ( FTDP-17), an autosomal, dominantly inherited neurodegenerative disorder caused by tau gene mutations, is neuropathologically characterized by intraneuronal filamentous inclusions of hyperphosphorylated tau protein. Biochemical and immunocytochemical analyses have shown that only mutant tau is deposited in patients harboring P301L missense mutation, whereas both wild-type and mutant tau are deposited in patients harboring R406W mutation (Miyasaka, T., Morishima-Kawashima, M., Ravid, R., Kamphorst, W., Nagashima, K., and Ihara, Y. (2001) J. Neuropathol. Exp. Neurol. 60, 872-884 and Miyasaka, T., Morishima-Kawashima, M., Ravid, R., Heutink, P., van Swieten, J. C., Nagashima, K., and Ihara, Y. ( 2001) Am. J. Pathol. 158, 373-379). Here we have tested the nucleation ability of monomeric tau and the seeding ability of fibrillogenic nuclei obtained from bacterially expressed human tau. P301L mutant tau showed a higher nucleation ability than wild-type tau, whereas R406W mutant tau shows similar ability to wild-type tau. Surprisingly, fibrillogenic nuclei composed of P301L mutant tau enhanced the assembly of P301L mutant tau into filaments but did not promote filament formation from wild- type tau. In contrast, nuclei composed of R406W mutant tau supported filament formation from both wild- type tau and R406W mutant tau, as did nuclei composed of wild- type tau. Proteolytic analyses indicated that the substructure of nuclei composed of P301L mutant tau was different from that of nuclei composed of wild- type or R406W mutant tau. Thus, the interaction between fibrillogenic nuclei and monomeric protein appears to play an important role in the mechanism of tau filament assembly.