EXPRESSION OF THE HUNTINGTONS-DISEASE (IT15) PROTEIN PRODUCT IN HD PATIENTS

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by expansion of a CAG repeat in the IT15 gene, leading to an ex panded glutamine repeat in the HD protein, The mechanism by which the expanded repeat causes expression of the disease is not known, though there do not appear to be changes in the mRNA levels, We have conducte d quantitative Western blot analyses of HD patients and controls. Expr ession of the IT15 protein is essentially equal in control and HD fron tal cortex. In caudate from HD patients, IT15 protein is decreased in parallel with the decrease in a neuronal marker, suggesting that loss of IT15 protein is secondary to neuronal loss, In order to determine e xpression of the two alleles of the IT15 protein we used Western blots of 4% polyacrylamide gels, Both alleles of the IT15 protein were expr essed at similar levels in HD lymphoblastoid cell lines and HD post-mo rtem hippocampus and cerebellum (regions relatively spared in HD), ind icating that even very long CAG repeats can be translated into polyglu tamine, In contrast, in cerebral cortex and caudate (regions severely affected in HD), in the longer expanded repeat cases the expanded alle le of the IT15 protein was present at a significantly lower level (com pared with the normal length allele), often with a smear of more slowl y migrating reactivity above it, These data suggest the possibility of altered structure, abnormal processing or abnormality of protein-prot ein interactions involving the IT15 protein with the expanded glutamin e repeat.