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Molecular analyses of cell death and vacuole formation that are induced by abnormal protein accumulation

异常蛋白质积累诱导的细胞死亡和液泡形成的分子分析

基本信息

批准号：
14370057
负责人：
KAKIZUKA Akira
金额：
$ 9.6万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370057/
关键词：
polyglutamine vacuole formation neuronal cell death AAA ATPase VCP amino acid modification Lewy body protein aggregates ポリグルタミ MJD プロセシング空胞変性小胞体小胞体ストレス

项目摘要

In neurodegenerative disorders, protein aggregates and vacuoles are almost universally found in degenerating neurons, suggesting the existence of similar molecular processes in, neuronal cell death. Indeed, 9 inherited neurodegenerative diseases, including Huntington disease have been shown to be caused by the expansion of CAG repeats encoding polyglutamines. We have identified VCP, a member of the AAA ATPase, as a key molecule in neurodegeneration. Namely, 1) VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease; 2) Profound deficits in VCP's ATPase activity are found to severely affect ER quality control, leading to abnormal ER expansion and cell death, phenotypes frequently observed in many neurodegenerative diseases; 3) VCP has a potential to unfold misfolded proteins; 4) several amino acid in VCP are modified; 5) Modified VCP shows different ATPase activities. These lines of evidence raise the possibility that excessive accumulation of abnormal proteins may inactivate, VCP's ATPase via its (mis)modification in several neurodegenerative disorders, eventually leading to the neurodegenerations. A proper regulation of VCP function is thus proposed to lead to novel treatments that are effective in a broad spectrum of neurodegenerative diseases.

在神经退行性疾病中，蛋白质聚集体和液泡几乎普遍存在于退化神经元中，这表明神经元细胞死亡中存在类似的分子过程。事实上，包括亨廷顿病在内的 9 种遗传性神经退行性疾病已被证明是由编码多聚谷氨酰胺的 CAG 重复序列的扩展引起的。我们已经确定 VCP（AAA ATP 酶的成员）是神经退行性疾病的关键分子。即，1）VCP与聚谷氨酰胺聚集体和其他蛋白质聚集体（例如帕金森病中的路易体）共定位； 2）VCP的ATP酶活性严重缺陷，严重影响内质网质量控制，导致内质网异常扩张和细胞死亡，这是许多神经退行性疾病中常见的表型； 3）VCP具有解折叠错误折叠蛋白质的潜力； 4)对VCP中的多个氨基酸进行修饰； 5) 修饰后的VCP表现出不同的ATP酶活性。这些证据提出了一种可能性，即异常蛋白质的过度积累可能会通过其在几种神经退行性疾病中的（错误）修饰而使 VCP 的 ATP 酶失活，最终导致神经退行性疾病。因此，建议对 VCP 功能进行适当调节，以开发出对广泛的神经退行性疾病有效的新疗法。