DIFFERENTIAL DISTRIBUTION OF THE NORMAL AND MUTATED FORMS OF HUNTINGTIN IN THE HUMAN BRAIN

Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion o f a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mut ation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution an d intracellular location as normal huntingtin, we analyzed immunohisto chemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous thr oughout the brain, but is not limited to vulnerable neurons in Hunting ton's disease, supporting the hypothesis that the presence of the muta ted huntingtin in a neuron is not in itself sufficient to lead to neur onal death. Moreover, whereas normal huntingtin is detected in some ne uronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expre ssion or processing of the mutated huntingtin in perikarya and nerve e ndings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.