Expanding horizons for treatment

Huntington’s disease is one of eight hereditary and progressive neurodegenerative disorders in which the underlying mutation is a CAG expansion in the coding sequence of the gene (figure). The mutation is a “trinucleotide expansion”—ie, the number of CAG triplets present in the mutated gene is greater than the number found in a normal gene. Additionally, the number of CAG triplets in the disease gene continues to increase as it is inherited. Huntington’s disease is an autosomal dominant disorder. Therefore, the expanded CAG repeat is usually present in only one of two alleles in the cell. Unaffected individuals can have 6–25 CAG triplets in both alleles, whereas in patients with Huntington’s, the disease allele contains 36–120 CAG triplets. The CAG triplet codes for the aminoacid glutamine. As the CAG repeat number grows, the growing polyglutamine tract produces a gene product, huntingtin, with increasingly aberrant properties, which kills brain cells that control movement. The mechanism by which the abnormal huntingtin destroys brain cells, or why cell death occurs preferentially in select brain regions, is poorly understood. However, a long polyglutamine tract creates an unusually sticky molecule, which binds to, and interferes with, cellular molecules and their functions. Therefore, huntingtin-mediated aggregation is probably part of the cell death mechanism. The loss of brain cells causes memory deficits and uncontrolled muscle movements (termed chorea) that are characteristic of the disorder. As disease progresses, patients lose the ability to walk, to speak, and to swallow. Disease character is strongly connected to the number of CAG triplets within the disease allele. Affected individuals with 36 triplets, for example, might develop mild features late in life, whereas those with more triplets will develop severe features at a younger age. In one affected family, a mother with a CAG repeat number of 55 developed uncontrolled muscle movement at 35. Her son inherited the faulty gene with an expansion of 72 CAG repeats, and developed similar symptoms at age 18. Once symptoms begin, death usually occurs within 15–20 years. Little more than antidepressants and neuroleptics are available to manage the symptoms of this relentless disease. However, research over the past decade has provided hope that more effective therapeutic strategies are possible. Energy depletion and deficits in mitochondria probably play a part in Huntington’s disease, and, as such, clinical trials are underway to assess the efficacy of co-enzyme Q, a nutritional supplement that improves energy production in mitochondria. Affected cells in Huntington’s disease include a specialised brain cell known as a medium spiny neuron. These cells contain many small “spines” that are rich in excitatory glutamate receptors. Too much excitation can lead to neuronal death. Thus, tests are being done to study the effects of remacemide, which blocks this receptor-mediated, excitatory pathway. Once neurons become badly damaged, they can activate pathways leading to programmed death. Blocking these pathways might improve survival of affected brain cells. Indeed, clinical trials are planned to test the efficacy of minocycline, an inhibitor of cell death, that has improved survival in animals. Treatment with these compounds, however, delays, but does not prevent, disease progression. Other developing strategies are aimed at a cure. Features of disease can be reversed, in animals, if expression of the disease allele can be shut-off. Inhibition of the expression of the mutant gene not only prevents disease progression in mice, but also reverses features of pathophysiology in animals that have developed disease. However, research has shown that the product of the normal gene is required for cell survival and development. Therefore, a major challenge is to find a molecule that can inhibit expression of the mutant gene while allowing expression of its normal counterpart. Finally, surgical strategies are being explored for transplantation of stem cells to replace lost neurons in the brain. Stem cells are derived from fetal tissue but have the potential to develop into normal brain cells if surgically implanted into the brain. These procedures are currently at the experimental stage, and we do not yet know if they are safe. However, embryonic grafts have improved motor functions in animals and in human beings. Although no effective therapy is around the corner, hope for an intervention is on the horizon. Regions of neuronal loss in Huntington’s disease (left), and relation between number of CAG repeats and pathophysiology of Huntington’s disease (right). Red regions=areas of neuronal loss in patients with between 36 and 120 CAG repeats. C/P=caudate/putamen, CTX=cortex, GP=globus pallidus, STN=subthalamic nucleus, VL=ventrolateral thalamic nucleus, SN=substantia nigra.