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GENES CELLS (2001) 6, 887-897.
Copyright © 2001 Blackwell Publishing or its licensors

Original Article

Initial process of polyglutamine aggregate formation in vivo

Y Kimura, S Koitabashi, A Kakizuka, and T Fujita

BACKGROUND: Polyglutamine expansion in protein is responsible for several inherited neuro-degenerative diseases. The expansion has toxic effects on neural cells as well as results in forming aggregates. Using yeast, we examined the initial process of polyglutamine aggregate formation in vivo. RESULTS: Following expression, polyglutamine tracts were of a soluble form during a lag period, and then formed insoluble complexes. The lag was prolonged and the formation of insoluble complex became slower by decreasing the number of polyglutamine tracts and by a treatment with guanidine hydrochloride. Gel filtration analysis revealed that the soluble polyglutamine existed in a small form. Formation of polyglutamine aggregates appeared to follow similar kinetics reported in the in vitro studies, where polyglutamine tracts self-aggregate in a length-, concentration- and time-dependent manner. However, in vivo, Hsp104 was required for the conversion from a soluble to an insoluble state. Without Hsp104, polyglutamine tracts tended to remain in a small soluble form, prolonging the lag. Moreover, the dependency on Hsp104 for aggregate formation was strong with the short polyglutamine tract, and decreased with the long polyglutamine tract. CONCLUSION: For polyglutamine aggregate formation, a balance of parameters including the length of the polyglutamine tract, Hsp104, and level of polyglutamine expression determined its efficiency.


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