Study on involvement of of tau-binding factors in neurodegeneration

tau结合因子参与神经退行性变的研究

• 批准号: 18591286
• 负责人: TANAKA Toshihisa
• 金额: $ 2.49万
• 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: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591286/
• 关键词: Tau urotein; 14-3-3 protein; Phosphorylation; Protein kinase

Neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease (AD) and other tauopathies including frontotemporal dementia (FTD) and corticobasal degeneration, and abnormally hyperphosphorylated tau protein is the major protein component of NFT. After finding of tau gene on chromosome 17 as a causative gene for familial FTD (FTDP-17), tau is thought to be essentially important for understanding of neurodegenerative processes in dementia. In brain of tauopathies tau is hyperphosphorylated and ubiquitinated, and self-assembles and forms filaments or aggregates, however the mechanisms of the involvement of tau in neurodegeneration are unclear.To understand the mechanisms of self-assembly of tau, we investigated the effects of phosphorylation of tau on the process self-assembly induced by 14-3-3. Phosphorylation of tau by protein kinase A (PKA) or protein kinase B (PKB), not glycogen synthase kinase-3, enhanced the binding of tau with 14-3-3, however PKA- or PKB-phosphorylation abolished the self-assembly of tau protein. And we investigated the effects of FTDP-17 mutations of tau on the process self-assembly induced by 14-3-3. The mutant tau (P301L, V337M and R406W) had higher affinity with 14-3-3 than wild type tau, and P301L tau induced the highest self-assembly level than others in the presence of 14-3-3. Our results suggest that phosphorylation and mutations of tau might play an important role in self-assembly of tau.

神经元缠结是阿尔茨海默病（AD）和其他tau蛋白病（包括额颞叶痴呆（FTD）和皮质基底节变性）的神经病理学标志，异常过度磷酸化的tau蛋白是NFT的主要蛋白组分。在发现17号染色体上的tau基因是家族性FTD（FTDP-17）的致病基因后，认为tau对理解痴呆的神经退行性过程至关重要。在tau蛋白病的脑组织中，tau蛋白被过度磷酸化和泛素化，并自组装形成纤维或聚集体，但tau蛋白参与神经退行性变的机制尚不清楚，为了了解tau蛋白自组装的机制，我们研究了tau蛋白磷酸化对14-3-3诱导的tau蛋白自组装过程的影响。蛋白激酶A（PKA）或蛋白激酶B（PKB）而非糖原合成酶激酶-3磷酸化tau增强tau与14-3-3的结合，然而PKA或PKB磷酸化消除tau蛋白的自组装。我们研究了tau蛋白的FTDP-17突变对14-3-3诱导的自组装过程的影响。与野生型tau相比，突变型tau（P301 L、V337 M和R406 W）与14-3-3的亲和性更高，并且在14-3-3存在下，P301 L tau诱导的自组装水平最高。我们的研究结果表明，tau蛋白的磷酸化和突变可能在tau蛋白的自组装中发挥重要作用。

项目成果

Biological markers as outcome measures for Alzheimer's disease interventions--real problems and future possibilities

生物标记作为阿尔茨海默病干预措施的结果测量——现实问题和未来的可能性

• 发表时间: 2007
• 期刊: Int Psychogeriatr 19(3)
• 作者: Takeda M;Okochi M;Tagami S;Tanaka T;Kudo T
• 通讯作者: Kudo T

Biological markes as outcome measures for Alzheimer' s disease interventions-real problems and future possibilities.

生物标记作为阿尔茨海默氏病干预结果的衡量标准——现实问题和未来的可能性。

• 发表时间: 2007
• 期刊: Int Psychogeriatr. 19
• 作者: Takeda M;Okochi M;Tagami S;Tanaka T;Kudo T.
• 通讯作者: Kudo T.

The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease.

DYRK1A 基因编码于 21 号染色体唐氏综合症关键区域，在阿尔茨海默病中充当 β-淀粉样蛋白生成和 tau 磷酸化之间的桥梁。

• 发表时间: 2007
• 期刊: Hum Mol Genet. 16(1)
• 作者: Kimura R;Kamino K;Yamamoto M;Nuripa A;Kida T;Kazui H;Hashimoto R;Tanaka T;Kudo T;Yamagata H;et al
• 通讯作者: et al

"Biological markers for diagnosis of MCI and neurodegenerative dementia", Functional and Moleculart Imaging of Stroke and Dementia

“诊断 MCI 和神经退行性痴呆的生物标志物”，中风和痴呆的功能和分子成像

• 发表时间: 2006
• 作者: Takeda M;Kudo T;Tanaka T;Kamino K;Okochi M;Tagami S
• 通讯作者: Tagami S

Toll-like receptor 3 mediated hyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells.

Toll 样受体 3 介导人 SH-SY5Y 神经母细胞瘤细胞中 tau 蛋白的过度磷酸化。

• 发表时间: 2006
• 期刊: Psychiatry and Clinical Neuroscience 60
• 作者: Nessa BN;Tanaka T;Kamino K;Sadik G;Ansar AB;Kimura R;Tanii H;Okochi M;Morihara T;Tagami S;Kudo T;Takeda M.
• 通讯作者: Takeda M.