Abstract
Polyglutamine diseases, such as Huntington disease (HD) and spinocerebellar ataxia 1 and 3, are autosomal dominant neurodegenerative disorders. They are caused by CAG trinucleotide repeat expansions that are translated into abnormally long polyglutamine tracts. One of the pathological hallmarks in polyglutamine diseases is the formation of intranuclear inclusions of polyglutamine-containing proteins in the brain. We developed a novel in vitro model system for polyglutamine diseases using myoglobin as a host protein. We searched for small molecules that inhibit polyglutamine-mediated aggregation by in vitro screening with a mutant myoglobin containing a 35 polyglutamine repeat. The screening assay revealed that disaccharides have a potential to inhibit polyglutamine-induced protein aggregation and to increase survival in a cellular model of HD. Oral administration of trehalose, the most effective disaccharide in vitro, decreased polyglutamine aggregates in the cerebrum and liver, improved motor dysfunction and extended life span in a transgenic mouse model of HD. In vitro experiments suggest that the beneficial effects of trehalose result from its ability to bind and stabilize polyglutamine-containing proteins. The lack of toxicity and high solubility, coupled with its efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases.
