HUNTINGTONS-DISEASE GENE - REGIONAL AND CELLULAR EXPRESSION IN BRAIN OF NORMAL AND AFFECTED INDIVIDUALS

Huntington's disease (HD) is an autosomal dominant disorder characteri zed by involuntary movements, dementia, and progressive, global, but r egionally accentuated, brain atrophy. The disease affects the striatum most severely. An expansion of a trinucleotide repeat on chromosome 4 p16.3 within the coding region of a gene termed IT15 has been identifi ed as the mutation causing HD. The normal function of IT15 and the mec hanisms by which the presence of the mutation causes HD are unknown. A lthough IT15 expression has been detected in the brain, as well as in other organ tissues,. by Northern blot and in situ hybridization, it i s not known whether a preferential regional or cellular expression of IT15 exists within the central nervous system of normal, affected, and presymptomatic individuals. Using quantitative in situ hybridization methods, we examined extensively the regional and cellular expression of IT15. In controls, IT15 expression was observed in all brain region s examined with the highest levels seen in cerebellum, hippocampus, ce rebral cortex, substantia nigra pars compacta. and pontine nuclei. Exp ression in the striatum was intermediate and expression in the globus pallidus was low. IT15 was expressed predominantly in neurons; a low b ut significant level of expression was seen in glial cells. Analysis o f grain counts per square micrometer in neurons showed that the region al differences in the level of mRNA expression were related to density and size of neurons in a given region and not primarily to difference s in levels of mRNA expression in individual cells after correction fo r cell size. Neurons susceptible to degeneration in HD did not selecti vely express high levels of IT15 mRNA. In HD brains (grades 2-4), the distribution and levels of IT15 mRNA were comparable with controls in all areas except in neostriatum where the intensity of labeling was si gnificantly reduced. Presymptomatic HD brains had a striatal expressio n similar to controls and surviving striatal neurons in more advanced HD had an expression of IT15 within normal limits. It is apparent from these results that the presence of expanded trinucleotide repeats in IIB does not result in the absence of IT15 mRNA expression or in alter ed patterns or levels of expression. The lack of correlation between t he levels of IT15 mRNA expression and susceptibility to degeneration i n HD strongly suggests that the mutant gene acts in concert with other factors to cause the distinctive pattern of neurodegeneration in HD.