LENGTH OF HUNTINGTIN AND ITS POLYGLUTAMINE TRACT INFLUENCES LOCALIZATION AND FREQUENCY OF INTRACELLULAR AGGREGATES

It is unclear how polyglutamine expansion is associated with the patho genesis of Huntington disease (HD). Here. we provide evidence that pol yglutamine expansion leads to the formation of large intracellular agg regates in vitro and in vivo. In vitro these huntingtin-containing agg regates disrupt normal cellular architecture and increase in frequency with polyglutamine length. Huntingtin truncated at nucleotide 1955, c lose to the caspase-3 cleavage site, forms perinuclear aggregates more readily than full-length huntingtin and increases the susceptibility of cells to death following apoptotic stimuli. Further truncation of h untingtin to nucleotide 436 results in both intranuclear and perinucle ar aggregates. For a given protein size, increasing polyglutamine leng th is associated with increased cellular toxicity. Asymptomatic transg enic mice expressing full-length huntingtin with 138 polyglutamines fo rm exclusively perinuclear aggregates in neurons. These data support t he hypothesis that proteolytic cleavage of mutant huntingtin leads to the development of aggregates which compromise cell viability, and tha t their localization is influenced by protein length.