The mechanisms of aggregation, accumulation and degradation of the genetically causative protein related to familial dementia diseases

家族性痴呆疾病相关遗传致病蛋白的聚集、积累和降解机制

基本信息

批准号：
21390333
负责人：
TAKEDA Masatoshi
金额：
$ 11.56万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

Tau protein is hyperphosphorylated, ubiquitinated and accumulated in FTDP-17 brains, however mechanisms of the accumulation is still unclear. To understand the involvement of proteases in metabolisms of tau protein, some of protease inhibitors were employed in cultured cells. Pulse-chase experiments revealed proteolysis of tau protein was attenuated when treated with puromycin. And increased tau protein levels were also observed in cells treated with siRNA to puromycin-sensitive aminopeptidase(PSA) for inhibition of its expression. Those data suggest that PSA is a protease which regulates proteolysis of tau predominantly in cells. The protein metabolism of tau containing FTDP-17 mutations was also investigated employing pulse-chase experiments and attenuated proteolysis of tau was observed in the cells transfected with the mutant tau. Phosphorylation of tau at Thr231, Ser396 and Ser409 was increased in the cells transfected with V337M, R406W, and R406W mutant tau gene, respectively. These results suggest that attenuated proteolysis of FTDP-17 mutant tau might be explained by the increased phosphorylation levels resulting in resistance to proteolysis. Furthermore, in cells treated with fumagilin, an inhibitor to methionine aminopeptidase, tau protein with N-terminal methionine increased similar to puromicin-treated cells, suggesting that aminoterminal processing of tau protein is important for tau degradation.

tau蛋白是磷酸化的，泛素化的，并积聚在FTDP-17大脑中，但是积累的机制尚不清楚。为了了解蛋白酶在tau蛋白的代谢中的参与，一些蛋白酶抑制剂用于培养细胞中。脉搏追踪实验表明，用嘌呤霉素治疗时会减弱tau蛋白的蛋白水解。在用siRNA对紫霉素敏感氨基肽酶（PSA）处理的细胞中，还观察到升高的tau蛋白水平，以抑制其表达。这些数据表明，PSA是一种蛋白酶，可调节细胞中Tau的蛋白水解。还研究了使用脉搏疗法实验的含有FTDP-17突变的Tau的蛋白质代谢，并在用突变体TAU转染的细胞中观察到Tau的蛋白水解。在用V337M，R406W和R406W突变体Tau基因转染的细胞中，TH231，Ser396和Ser409处TAU的磷酸化增加了。这些结果表明，FTDP-17突变体TAU的减弱蛋白水解可以通过磷酸化水平升高，从而导致对蛋白水解的耐药性来解释。此外，在用富马吉蛋白治疗的细胞（一种抑制剂对蛋氨酸氨基肽酶的抑制剂）中，具有N末端蛋氨酸的tau蛋白与铜蛋白处理的细胞相似，这表明tau蛋白的氨基酸加工对TAU降解很重要。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PIB-PET images, compared with MR, FDG-PET, and IMP-SPECT images, of a patient with Alzheimer' s disease with presenilin-1 mutation(Met233Leu) showing a new phenotype

具有早老蛋白-1 突变 (Met233Leu) 的阿尔茨海默病患者的 PIB-PET 图像与 MR、FDG-PET 和 IMP-SPECT 图像相比，显示出新的表型

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Takaya M;Tanaka T;Ataka S;Shimada H;Morihara T;Miki T;Kazui H;Takeda M
通讯作者：
Takeda M

Identification of a gene which controls Abeta accumulation using App Tg mice with mixed genetic background

使用具有混合遗传背景的 App Tg 小鼠鉴定控制 Abeta 积累的基因

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Morihara T;Hayashi N;Yokokoji M;Fukusyo E;Tanimukai H;Tagami S;Okochi M;Tanaka T;Kudo T;Takeda M
通讯作者：
Takeda M

Protein kinase C stabilizes X-linked inhibitor of apoptosis protein(XIAP) through

蛋白激酶 C 通过稳定 X 连锁凋亡抑制蛋白 (XIAP)

DOI：
发表时间：
2011
期刊：
phosphorylation at Ser87 to suppress apoptotic cell death
影响因子：
0
作者：
Kato K;Tanaka T;Sadik G;Baba M;Maruyama D;Yanagida K;Kodama T;Morihara T;Tagami S;Okochi M;Kudo T;Takeda M
通讯作者：
Takeda M

Genomics and Cognitive Function of the elderly

老年人的基因组学和认知功能