Kimura Yoko, Kakizuka Akira
Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
IUBMB Life. 2003 Jun;55(6):337-45. doi: 10.1080/1521654032000114339.
The polyglutamine diseases, a group of diseases currently thought to consist of nine inherited neurodegenerative diseases, are caused by the expansion of unstable CAG trinucleotide repeats that code for polyglutamine tracts in the responsible genes. These diseases are now recognized as being of a type with conformationally abnormal or amyloid-related proteins, and thus are called 'conformational diseases'. Recently, many studies using cell cultures and model organisms have suggested that the two major machineries for protein quality control (the molecular chaperone and the protein degradation machineries) play important roles in the pathogenesis of the polyglutamine diseases. Interestingly, molecular chaperones have been shown to behave in totally different ways in these studies, namely in suppressing as well as enhancing neurodegeneration or cell death. These apparently opposite actions of molecular chaperones suggest that a certain balance between the activities of molecular chaperones and the expression level of polyglutamine is an important determinant of the pathogenesis. In this review, we summarize recent findings on such ambiguous effects of molecular chaperones on polyglutamine diseases, and discuss possible mechanisms by which molecular chaperones, especially VCP, are involved in the pathogenesis.
多聚谷氨酰胺疾病是目前认为由九种遗传性神经退行性疾病组成的一组疾病，由不稳定的CAG三核苷酸重复序列扩增引起，这些重复序列在相关基因中编码多聚谷氨酰胺片段。这些疾病现在被认为是与构象异常或淀粉样蛋白相关的蛋白质类型，因此被称为“构象疾病”。最近，许多使用细胞培养和模式生物的研究表明，蛋白质质量控制的两个主要机制（分子伴侣和蛋白质降解机制）在多聚谷氨酰胺疾病的发病机制中起重要作用。有趣的是，在这些研究中分子伴侣表现出完全不同的行为方式，即在抑制以及增强神经退行性变或细胞死亡方面。分子伴侣这些明显相反的作用表明，分子伴侣活性与多聚谷氨酰胺表达水平之间的某种平衡是发病机制的重要决定因素。在这篇综述中，我们总结了分子伴侣对多聚谷氨酰胺疾病这种模糊作用的最新发现，并讨论了分子伴侣特别是VCP参与发病机制的可能机制。
