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

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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.