CAG EXPANSION AFFECTS THE EXPRESSION OF MUTANT HUNTINGTIN IN THE HUNTINGTONS-DISEASE BRAIN

A trinucleotide repeat (GAG) expansion in the huntingtin gene causes H untington's disease (HD). In brain tissue from HD heterozygotes with a dult onset and more clinically severe juvenile onset, where the larges t expansions occur, a mutant protein of equivalent intensity to wild-t ype huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protei n to nerve endings. The increased size of mutant huntingtin relative t o the wild type was highly correlated with CAG repeat expansion, there by linking an altered electrophoretic mobility of the mutant protein t o its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutan t protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA l evel for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain a nd is harmful only to some neurons.