Huntington's Disease

Mutant Huntingtin Protein and Intracellular Abnormalities

The basic underlying defect in HD remains unclear. However, the disease processes associated with HD are thought to be caused by a toxic "gain of function," meaning that the mutated gene's protein (mutant huntingtin) interferes with normal cellular functioning. For example, evidence suggests that abnormal huntingtin may induce inappropriate, genetically programmed nerve cell death (apoptosis). In addition, researchers indicate that expansion of the amino acid glutamine within the huntingtin protein is associated with accumulations or inclusions of mutant huntingtin and an associated protein (ubiquitin) within the nucleus of neurons in the basal ganglia (i.e., striatum) and cerebral cortex. Evidence suggests that these inclusions may form as cells attempt to inactivate the toxic huntingtin protein.

In addition, investigators have demonstrated that caspase-1, an enzyme involved in controlling cellular death, is activated in the brain in patients with HD and a transgenic mouse model of the disease. Injection of a caspase inhibitor into the brains of transgenic mice was associated with delayed disease progression and prolonged life. In mice with genetically programmed reductions in caspase-1 activity, there were delays in nerve cell damage and in symptom onset, with extended survival. Such findings suggest the role caspase-1 may play in HD disease progression—and that blocking the action of caspase-1 may have implications for human disease.