WIDESPREAD EXPRESSION OF HUNTINGTONS-DISEASE GENE (IT15) PROTEIN PRODUCT

Huntington's Disease (HD) is caused by expansion of a CAG repeat withi n a putative open reading frame of a recently identified gene, IT15. W e have examined the expression of the gene's protein product using ant ibodies developed against the N-terminus and an internal epitope. Both antisera recognize a 350 kDa protein, the predicted size, indicating that the CAG repeat is translated into polyglutamine. The HD protein p roduct is widely expressed, most highly in neurons in the brain. There is no enrichment in the striatum, the site of greatest pathology in H D. Within neurons, the protein is diminished in nuclei and mitochondri a and is present in the soluble cytoplasmic compartment, as well as lo osely associated with membranes or cytoskeleton, in cell bodies, dendr ites, and axons. It is concentrated in nerve terminals, including term inals within the caudate and putamen. Thus, the normal HD gene product may be involved in common intracellular functions, and possibly in re gulation of nerve terminal function. The product of the expanded allel e is expressed, consistent with a gain of function mechanism for HD at the protein level.