Polyglutamine Residues from Machado-Joseph Disease Gene Enhance Formation of Aggregates of GST-Polyglutamine Fusion Protein in E. coli

Several neurodegenerative diseases such as Huntington's disease, dentatorubralpallidoluysian atrophy, spinobulbar muscular atrophy, Machado-Joseph disease, and spinocerebellar ataxias type 1 are associated with the aggregation of expanded glutamine repeats within their proteins. Generally, in clinically affected individuals, the expansion of the polyglutamine sequences is beyond 40 residues. To address the length of polyglutamine that forms aggregation, we have constructed plasmids encoding glutathione S-transferase (GST) Machado-Joseph disease gene fusion proteins containing polyglutamine and investigated the formation of aggregates in E. coli. Surprisingly, even $(Gin)_8$, in the normal range as well as $(Gin)_{65}$ in the pathogenic range enhanced the formation of insoluble protein aggregates, whereas $(Ser)_8$, and $(Aia)_8$, did not form aggregates. Our results indicate that the formation of protein aggregates in GST-polyglutamine proteins is specifically mediated by the polyglutamine repeat sequence within their protein structure. Our study may contribute to the understanding of the molecular mechanism of the formation of protein aggregates in neurodegenerative disorders and the development of preventative strategies.