Project Overview

Huntington disease (HD) is an inherited disorder that causes progressive malfunctioning and death of parts of the brain that control movement, reasoning and emotions. HD patients also suffer from depression and personality changes.  There is no cure for HD. Symptoms progress steadily until patients can no longer conduct a normal life and eventually die. The cause of HD is known: people with HD have a mutated protein called huntingtin which becomes toxic. One of the reasons why mutated huntingtin is toxic is that it causes the brain to produce insufficient amounts of a molecule called GM1 that is important for healthy brain function. Supplementation of GM1 to mouse models of HD dramatically improves the symptoms of the disease and slows down the underlying neurodegenerative process. This suggests that GM1 could be a potential treatment for HD.  In order to facility clinical use of GM1 or similar molecules, the first goal of our proposal is to determine how exactly GM1 works.  We will look at thousands of proteins in brain cells from mice with HD and from HD patients, and determine which proteins are beneficially affected by GM1. This will help us to understand how GM1 works and whether there are additional molecules that could be exploited for HD therapy. We will also determine whether GM1 exerts its therapeutic activity by regulating the function of the immune cells of the brain and inflammation. A second goal of the proposal is to determine whether the levels of GM1 (and related molecules) can be monitored in the blood and brain fluid of HD patients to gain information on disease and brain damage progression. This information would help in clinical trials, by showing whether the drugs tested are working decreasing mutated huntingtin toxicity.