NORMAL AND EXPANDED HUNTINGTONS-DISEASE GENE ALLELES PRODUCE DISTINGUISHABLE PROTEINS DUE TO TRANSLATION ACROSS THE CAG REPEAT

Background: An expanded CAG trinudeotide repeat is the genetic trigger of neuronal degeneration in Huntington's disease (HD), but its mode o f action has yet to be discovered. The sequence of the HD gene places the CAG repeat near the 5' end in a region where it may be translated as a variable polyglutamine segment in the protein product, huntingtin . Materials and Methods: Antisera directed at amino acid stretches pre dicted by the DNA sequence upstream and downstream of the CAG repeat w ere used in Western blot and immunohistochemical analyses to examine h untingtin expression from the normal and the HD allele in lymphoblasto id cells and postmortem brain tissue. Results: CAG repeat segments of both normal and expanded IID alleles are indeed translated, as part of a discrete similar to 350-kD protein that is found primarily in the c ytosol. The difference in the length of the N-terminal polyglutamine s egment is sufficient to distinguish normal and HD huntingtin in a West ern blot assay. Conclusions: The HD mutation does not eliminate expres sion of the HD gene but instead produces an altered protein with an ex panded polyglutamine stretch near the N terminus. Thus, HD pathogenesi s is probably triggered by an effect at the level of huntingtin protei n.