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Functional analyses of VCP protein in neuronal cell death

VCP蛋白在神经细胞死亡中的功能分析

基本信息

批准号：
16390092
负责人：
KAKIZUKA Akira
金额：
$ 9.66万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390092/
关键词：
VCP neuronal cell death amino acid modification oxidation protein aggregates AAA ATPase polyglutmamine 神経変性疾患ミスセンス変異 IBMPFD 凝集体形成

项目摘要

Recent molecular analyses on human neurodegenerative disorders have revealed several common features such as accumulation of abnormal protein aggregates, cytoplasmic vacuolizations, neuronal cell death etc. We have analyzed the molecular bases of such disorders especially polyglutamine diseases, and have identified VCP protein, an AAA class ATPase, as a candidate for a sensor for the accumulation of abnormal proteins as well as for a mediator of cell death. Namely, 1)VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease, 2)the expression of ATPase activity-negative VCP in nueoronal cells induces ER-derived vacuoles and cell death, 3)several amino acids in VCP are modified by phoshprylations, acetylations and oxidations, 4)such modification can change VCP ATPase activities and its intra cellular localization, 5)especially, oxidized VCP at the 522 cysteine loses its ATPase activities, 6)depending upon the levels of soluble aggregates-prone proteins, VCP can modulate the aggregate formation, indicating dual VCP functions as an aggregate formase and an unfoldase. Further molecular analyses on VCP would lead to clues for further understanding as well as for novel treatments of neurodegenerative disorders such as polyglutamine diseases and Parkinson disease.

最近对人类神经退行性疾病的分子分析揭示了几个共同的特点，如异常蛋白质聚集体的积累，胞质空泡化，神经元细胞死亡等，我们已经分析了这种疾病的分子基础，特别是多聚谷氨酰胺疾病，并已确定VCP蛋白，AAA类ATP酶，作为一个候选人的传感器异常蛋白质的积累，以及为调解员的细胞死亡。即1）VCP与多聚谷氨酰胺聚集体和其它蛋白质聚集体（如帕金森病中的路易体）共定位，2）ATP酶活性阴性的VCP在神经细胞中的表达诱导ER源性空泡和细胞死亡，3）VCP中的几种氨基酸通过磷酸化、乙酰化和氧化被修饰，4）这种修饰可以改变VCP ATP酶活性及其在细胞内的定位，5）特别地，在522位半胱氨酸处氧化的VCP失去其ATP酶活性。6）取决于可溶性聚集体倾向蛋白的水平，VCP可以调节聚集体的形成，表明VCP作为聚集体形成酶和解折叠酶的双重功能。对VCP的进一步分子分析将为进一步了解和治疗神经退行性疾病如多聚谷氨酰胺病和帕金森病提供线索。