earticle

영어

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The main cause of HD is assumed to be the mutation in the gene coding for huntingtin (Htt), and the mutated Htt contains an abnormally expanded polyglutamine stretch (polyQ>35), which tends to aggregate into insoluble amyloid-like fibrils. Many attempts were made to inhibit the polyglutamine-induced protein aggregation, and the non-reducing disaccharide trehalose was reported to alleviate the disease symptoms of HD transgenic mice. However, trehalose is known to be rapidly hydrolysed to glucose by trehalase enzyme present in the small intestine, and its uptake into tissues is regarded to be very low. In addition, there is no evidence that trehalose can cross the blood-brain barrier (BBB). Here we show that BBB-permeable trehalose derivatives could be prepared by applying the delivery methods which are previously developed before, and the derivatives were found to efficiently prevent the aggregation of polyQ in the transfected HEK293 cells. Furthermore, the derivative (TD-G6), when given ad libitum to a transgenic mouse model of HD (Tg R6/2), was found to significantly prolong lifespan, improve motor functions and reduce the inclusion bodies in the mouse brain compared with the trehalose control.