The disease, first described by George Huntigton, is a result from a mutation in a gene called huntingtin found on chromosome 4, which contains CAG triplet coding for glutamine repeated dozens of times: polyglutamine-induced protein aggregation is the key biochemical disorder.

Inhibition of polyglutamine-induced protein aggregation could provide treatment options. Motomasa Tanaka, Yoko Machida, Sanyong Niu, Tetsurou Ikeda, Nihar R Jana, Hiroshi Doi, Masaru Kurosawa, Munenori Nekooki & Nobuyuki Nukina showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation (Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease, Nature Medicine 10, 2, 148  154, February 2004). The authors 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. They 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 in this work thus provides a new therapeutic strategy for polyglutamine diseases.



BM&L-February 2004