THE INFLUENCE OF HUNTINGTIN PROTEIN SIZE ON NUCLEAR-LOCALIZATION AND CELLULAR TOXICITY

Huntington disease is an autosomal dominant neurodegenerative disorder caused by the pathological expansion of a polyglutamine tract. In thi s study we directly assess the influence of protein size on the format ion and subcellular localization of huntingtin aggregates. We have cre ated numerous deletion constructs expressing successively smaller frag ments of huntingtin and show that these smaller proteins containing 12 8 glutamines form both intranuclear and peri nuclear aggregates. In co ntrast, larger NH2-terminal fragments of huntingtin proteins with 128 glutamines form exclusively perinuclear aggregates. These aggregates c an form in the absence of endogenous huntingtin. Furthermore, expressi on of mutant huntingtin results in increased susceptibility to apoptot ic stress that is greater with decreasing protein length and increasin g polyglutamine size. As both intranuclear and perinuclear aggregates are clearly associated with increased cellular toxicity, this supports an important role for toxic polyglutamine-containing fragments formin g aggregates and playing a key role in the pathogenesis of Huntington disease.