The Role of stress proteins in the aggregation and cytotoxicity of polyglutamine

聚谷氨酰胺病是由编码聚谷氨酰胺的扩张型不稳定CAG重复序列在相关基因中的表达引起的。这些疾病被认为是具有构象异常或淀粉样蛋白相关蛋白的类型。我们发现VCP/p97是一种AAA^+超家族蛋白，在体外可与聚谷氨酰胺直接结合，并在果蝇模型中表达，可促进聚谷氨酰胺对神经细胞的降解。我们还发现，在培养的细胞系统中，空泡的形成是细胞死亡的标志之一，随后是多聚谷氨酰胺的表达。HSP104是AAA^+超家族蛋白的另一个成员，在酵母中表达的聚谷氨酰胺的聚集形成需要HSP104。由于聚谷氨酰胺在不同的系统中以淀粉样蛋白的形式存在，这些结果表明一些分子伴侣可能促进了聚谷氨酰胺的淀粉样蛋白的形成。我们进一步研究了这些分子伴侣是如何作用于聚谷氨酰胺的。我们发现，HSP 104需要一定量的预先存在的聚谷氨酰胺聚集体来增强聚谷氨酰胺聚集。

The polyglutamine diseases are caused by the expression of expanded unstable CAG repeats that code for polyglutamine in the responsible genes. These diseases are recognized as a type with a conformationally abnormal or amyloid-related proteins. We identified VCP/p97, one of AAA^+ superfamily proteins, that directly binds to polyglutamine in vitro, and that functions as an enhancer of neurodegeration by polyglutamine expressed in a fly model. We also found that vacuolar formation is one of hallmarks followed by cell death by the expression of polyglutamine in cultured cell systems. Hsp104, another member of AAA^+ superfamily proteins, is required for aggregate formation of polyglutamine expressed in yeast. As polyglutamine takes a form of amyoid in various systems, these results suggest a possibility that some molecular chaperones facilitate amyloid formation of polyglutamines. We further investigated how these molecular chaperones work on polyglutamine. We found that a certain amount of pre-existing polyglutamine aggregates are required for Hsp 104 to enhance the polyglutamine aggregation.