Scientific approaches to Huntington's disease.

Abstract

Huntington's Disease (HD) is a progressive neurologic disorder transmitted as autosomal dominant. The symptoms of HD, which typically appear in midlife, include disturbances in movement, psychiatric symptoms, and a progressive dementia. Neuropathologic studies indicate a distinct pattern of neuronal degeneration in HD that affects many areas of the brain but consistently and severely involves the basal ganglia including the caudate, putamen, and globus pallidus. The basal ganglia undergo a progressive atrophy due to degeneration of intrinsic neurons that results in ventricular enlargement. Over the last decade, detailed neurochemical analyses have been carried out on the brains of patients who have died with HD. These studies have demonstrated the selective degeneration of chemically defined neuronal systems including the striatal cholinergic intrinsic neurons, the striatal nigral GABAergic pathway, and striatal peptidergic neurons with the relative sparing of other systems such as the nigrostriatal pathway. These findings have resulted in a better understanding of the pathophysiologic basis for the movement disorder of HD and have led to the development of pharmacologic strategies to correct the synaptic neurochemical imbalances. Recent studies have begun to focus on mechanisms responsible for the selective neuronal degeneration in HD. One promising hypothesis evolved from the finding that intrastriatal injections of excitatory amino acid analogues reproduces the neurochemical and histologic pathology of HD in experimental animals; as a consequence, it has been hypothesized that dysfunction of excitatory amino acid neurotransmission may cause the selective neuronal degeneration of HD. Another hypothesis involves an abnormality of the plasma membrane based upon observations of differences in membrane characteristics in fibroblasts and red blood cells from HD patients as compared to suitable controls. The ultimate goals of these studies are to develop methods for identifying presymptomatic carriers of the HD gene as well as strategies for preventing the neuronal degeneration associated with expression of the gene.