Grant: Doctoral Research Award - Priority Announcement: Huntington Disease

Huntington disease (HD) is a degenerative disease starting in mid-life that affects the neurons of an area of the brain called the striatum, which regulates movement. HD affects the part of the striatum responsible for inhibiting unwanted movement such that the primary symptom of HD is chorea or involuntary movement. There are presently no effective treatments or cures and death occurs, on average, 15 years after disease onset. HD is caused by an inherited mutation in the huntingtin gene, where a short sequence at the beginning of the gene is multiplied more than 36 times. The mutation has many effects on the function of the huntingtin protein (htt), including interfering with how it interacts with other proteins. One of these other proteins is Huntingtin Interacting Protein 14 (HIP14). HIP14 is a "PAT" which is a type of enzyme that adds a fatty acid to other proteins, including htt, in a process called palmitoylation. This process controls where in the cell a protein is located, like the address on an envelope, and what function it performs at that location. In a mouse model of HD, htt and other proteins are less palmitoylated. We have created a genetically modified mouse model that lacks the HIP14 gene to determine if HIP14 is involved in HD. This mouse model is born with a very severe form of HD; however, because people and HD model mice are not born with the disease, we are unable to definitively show that HIP14 is involved in HD. We are therefore engineering a new kind of mouse model called a "conditional knockout" mouse that works a little like a light switch. We will be able to "turn off" HIP14 when and where we want like turning a light off in one room but not another. We will then look for the symptoms of HD in this mouse model.