Functional analyses of VCP protein in neuronal cell death

最近对人类神经退行性疾病的分子分析揭示了一些共同的特征，如异常蛋白聚集、细胞质空泡化、神经细胞死亡等。我们分析了这些疾病特别是多谷氨酰胺疾病的分子基础，并发现VCP蛋白是一个AAA类ATPase，既是异常蛋白积累的传感器，也是细胞死亡的中介。也就是说，在帕金森病中，VCP与多聚谷氨酰胺聚集体和其他蛋白质聚集体(如路易体)共定位，2)ATPase活性阴性的VCP在核细胞中的表达导致内质网衍生的空泡和细胞死亡，3)VCP中的几个氨基酸被磷酸化、乙酰化和氧化修饰，4)这种修饰可以改变VCP的ATPase活性及其在细胞内的定位，5)尤其是522位半胱氨酸的氧化VCP失去了ATPase活性，6)VCP可以调节聚集的形成，这表明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以及神经退行性疾病的新疗法，如多谷氨酰胺病和帕金森病提供线索。

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.