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Molecular mechanism of the qualify control of proteins

蛋白质质量控制的分子机制

基本信息

批准号：
17028032
负责人：
TOHYAMA Masaya
金额：
$ 31.49万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

In this research, we examined the involvement of to the endoplasmic reticulum (ER) stress in both familial and sporadic Alzheimer's disease (AD). As the resulrts, we showed that familial AD-linked presenilin-1 (PS1) mutation induced the fragility to the ER stress and that one of the presenilin-2 (PS2) splice valiants (PS2V), which were observed in the sporadic AD patient brains, also caused the fragility to the ER stress. Further studies elucidated that hydroxy radicals caused by hypoxia, metals, etc. induced HMGAla protein resulting in the aberrant splicing variant (PS2V). These results suggest the inhibition of HMGAla protein as the new therapy for sporadic AD. Next, we investigated the apoptosis pathway under the ER stress and found that caspase-4 mediates ER stress induced- and β-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. Thus, we studied the activation of caspase-4 in the familial AD-linked PS1 mutation (ΔE9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (ΔE9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. These results also suggest that the regulation of activated caspase-4 should be one of the new therapies for AD.

在这项研究中，我们研究了内质网(ER)应激在家族性和散发性阿尔茨海默病(AD)中的作用。结果表明，家族性AD连锁早老素-1(PS1)突变导致了内质网应激的脆弱性，而在散发性AD患者脑中观察到的早老素-2(PS2)剪接验证基因(PS2V)也导致了内质网应激的脆弱性。进一步的研究表明，缺氧、金属等引起的羟基自由基诱导HMGAla蛋白产生异常剪接变异体(PS2V)。这些结果表明，抑制HMGAla蛋白可作为治疗散发性AD的新方法。接下来，我们研究了内质网应激下的细胞凋亡途径，发现Caspase-4介导了内质网应激诱导和β-淀粉样蛋白诱导的人细胞凋亡信号。这些结果提示，内质网应激和caspase-4参与了AD的细胞死亡。因此，我们研究了家族性AD连锁pS1突变(ΔE9)中caspase-4的激活情况。家族性AD连锁突变(ΔE9)的过表达促进了内质网应激下caspase-4的切割，表明caspase-4是参与AD细胞凋亡信号转导的关键caspase-4。我们还发现，caspase-4的过表达诱导了caspase-9和caspase-3的裂解，而没有从线粒体释放细胞色素-c。这些结果还表明，调节激活的caspase-4可能是治疗AD的新方法之一。

项目成果

期刊论文数量（233）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

p21Cipl/WAFl regulates radial axon growth and enhances motor functional recovery in the injured peripheral nervous system.

p21Cipl/WAF1调节径向轴突生长并增强受损周围神经系统的运动功能恢复。

DOI：
发表时间：
2006
期刊：
Brain Res. 1081(1)
影响因子：
0
作者：
Tomita K;Kubo T;Matsuda K;Madura T;Yano K;Fujiwara T;Tanaka H;Tohyama M;Hosokawa K.
通讯作者：
Hosokawa K.

RA410/Slyl suppresses MPP+ and 6-hydroxydopamine-induced cell death in SH-SY5Y cells.

RA410/Slyl 抑制 SH-SY5Y 细胞中 MPP 和 6-羟基多巴胺诱导的细胞死亡。

DOI：
发表时间：
2005
期刊：
Neurobiol Dis. 18(1)
影响因子：
0
作者：
Bando Y;Katayama T;Taniguchi M;Ishibashi T;Matsuo N;Ogawa S;Tohyama M.
通讯作者：
Tohyama M.

Cytoplasmic p21(Cipl/WAFl) regulates neurite remodeling by inhibiting Rho-kinase activity.

细胞质p21(Cipl/WAF1)通过抑制Rho激酶活性来调节神经突重塑。

DOI：
发表时间：
2002
期刊：
J Cell Biol. 158(2)
影响因子：
0
作者：
Tanaka H;Yamashita T;Asada M;Mizutani S;Yoshikawa H;Tohyama M.
通讯作者：
Tohyama M.

Possible involvement of the expression and phosphorylation of N-Myc in the induction of HMGA1a by hypoxia in the human neuroblastoma cell line

DOI：
10.1016/j.neulet.2004.10.039
发表时间：
2005-02
期刊：
Neuroscience Letters
影响因子：
2.5
作者：
Takeshi Yanagita;T. Manabe;H. Okuda;S. Matsuzaki;Y. Bando;T. Katayama;M. Tohyama
通讯作者：
Takeshi Yanagita;T. Manabe;H. Okuda;S. Matsuzaki;Y. Bando;T. Katayama;M. Tohyama

The p75 receptor is required for BDNF-induced differentiation of neural precursor cells