I. Gourfinkelan et al., DIFFERENTIAL DISTRIBUTION OF THE NORMAL AND MUTATED FORMS OF HUNTINGTIN IN THE HUMAN BRAIN, Annals of neurology, 42(5), 1997, pp. 712-719
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.