Grant: Project Grant

Huntington disease (HD) is a fatal neurodegenerative disease characterized by debilitating motor, cognitive and psychiatric symptoms. HD has been described as having symptoms of ALS, Alzheimer's disease and Schizophrenia at the same time. There is no cure for HD; however, great excitement lies ahead in the potential of so-called "gene-silencing drugs." Unlike the majority of brain disorders, HD has a known cause. A protein known as the huntingtin protein is found in everybody's brain, and appears to be important for the health of our brain cells. The huntingtin protein exists in two forms; one good, one bad. In individuals without HD, there is no bad huntingtin and plenty of good huntingtin. In HD, the good huntingtin is reduced and the bad huntingtin is present, resulting in the slow death of brain cells. As a result of this known cause, drugs can be developed that decrease the brain's production of huntingtin. Gene-silencing drugs do just this. However, one potential roadblock to successful HD treatment is the fact that many gene-silencing drugs are not specific for bad or good huntingtin, and will therefore reduce both the good and the bad. Reducing bad huntingtin will likely help delay or even prevent HD symptoms; however, we have no idea how the long-term reduction of good huntingtin affects the brain. Clinical trials with gene-silencing drugs are already underway, making it extremely important to prioritize basic research into studying the consequences of reducing good huntingtin. In the proposed research, we will use a variety of strategies to understand how good huntingtin reductions can alter the way our brain cells communicate with each other, and whether gene-silencing drugs that are specific for the bad protein should be used exclusively for the treatment of HD. Our research will help to make more informed decisions on which drugs should be administered to those suffering from this devastating disease.