Abstract
Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.
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Acknowledgements
We thank Y. Yamada (RIKEN Brain Science Institute) for maintenance of mice, N. Yoshiki and Y. Obata (RIKEN Tsukuba institute) for instruction on ovarian transplantation of R6/2 transgenic mice, and S. Sligar (University of Illinois) for allowing us to use the wild-type myoglobin expression plasmid. This study was partly supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (M.T. and N.N.) and of Health, Labour and Welfare (N.N), Japan, and by RIKEN President's Special Research Grant (M.T.).
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Tanaka, M., Machida, Y., Niu, S. et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10, 148–154 (2004). https://doi.org/10.1038/nm985
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DOI: https://doi.org/10.1038/nm985