Aoyagi Hirofumi, Hasegawa Masato, Tamaoka Akira
Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan.
J Biol Chem. 2007 Jul 13;282(28):20309-18. doi: 10.1074/jbc.M611876200. Epub 2007 May 25.
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.
与17号染色体相关的额颞叶痴呆和帕金森综合征（FTDP - 17）是一种由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存在过度磷酸化tau蛋白的丝状包涵体。生化和免疫细胞化学分析表明，在携带P301L错义突变的患者中只有突变型tau沉积，而在携带R406W突变的患者中野生型和突变型tau均有沉积（宫坂哲、森岛川真弓、拉维德、坎普霍斯特、长岛健、井原洋（2001年）《神经病理学与实验神经病学杂志》60卷，872 - 884页；宫坂哲、森岛川真弓、拉维德、休廷克、范·斯维滕、长岛健、井原洋（2001年）《美国病理学杂志》158卷，373 - 379页）。在此，我们测试了单体tau的成核能力以及从细菌表达的人tau获得的纤维状核的种子能力。P301L突变型tau比野生型tau表现出更高的成核能力，而R406W突变型tau与野生型tau表现出相似的能力。令人惊讶的是，由P301L突变型tau组成的纤维状核增强了P301L突变型tau组装成细丝的过程，但并未促进野生型tau形成细丝。相反，由R406W突变型tau组成的核支持野生型tau和R406W突变型tau形成细丝，由野生型tau组成的核也是如此。蛋白水解分析表明，由P301L突变型tau组成的核的亚结构与由野生型或R406W突变型tau组成的核不同。因此，纤维状核与单体蛋白之间的相互作用似乎在tau细丝组装机制中起重要作用。
