Grant: Project Grant

Huntington disease (HD) is a devastating inherited neurodegenerative disease that affects ~1 in 7000 Canadians. People with HD experience progressive movement, psychiatric and cognitive symptoms, and there are currently no treatments available to halt or slow the disease. HD is caused by a genetic mutation where a repeating C-A-G sequence of the DNA letter code of the Huntingtin gene is expanded to over 35 C-A-Gs in a row. This means that people with HD make an expanded version of the huntingtin protein which doesn't work properly, encoded by the faulty gene. Two of the key areas of study in HD research are firstly, to understand how the normal form of the huntingtin protein functions, and secondly, how this might differ for expanded form of the protein in people with HD. To try and tackle these questions, my team used very pure samples of the huntingtin protein that we make in the lab to begin to develop chemical tools that will enable studies of this mysterious protein molecule. In collaboration with a team in Tokyo, we used a cutting-edge binder discovery platform and have identified molecules that strongly interact with the huntingtin protein. Now, we propose to further characterise these binders, to develop them as chemical tools, and use them to study the huntingtin protein. In our proposed study, we will: - Closely study these new binder molecules to understand precisely how and where they attach to the huntingtin protein - Use the binder molecules to examine the huntingtin protein inside cells, to see where the protein is located and how its distribution may change during HD - Develop new versions of the binders with special handles to send huntingtin to the cellular trashcan or to fish different forms of huntingtin protein out of cells and study which other molecules are associated with it These tool molecules would be the first of their kind for studying the huntingtin protein and will be transformational for HD research in the studies that they enable.