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J. Cell Biol.,
Volume 141, Number 5, June 1, 1998 1097-1105
Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; and Department of Medical Genetics,
University of British Columbia, Vancouver, British Columbia, V6T 1Z4 Canada
Huntington disease is an autosomal dominant neurodegenerative disorder caused by the pathological expansion of a polyglutamine tract. In this study
we directly assess the influence of protein size on the
formation and subcellular localization of huntingtin aggregates. We have created numerous deletion constructs expressing successively smaller fragments of
huntingtin and show that these smaller proteins containing 128 glutamines form both intranuclear and perinuclear aggregates. In contrast, larger NH2-terminal
fragments of huntingtin proteins with 128 glutamines
form exclusively perinuclear aggregates. These aggregates can form in the absence of endogenous huntingtin. Furthermore, expression of mutant huntingtin results in increased susceptibility to apoptotic stress that
is greater with decreasing protein length and increasing
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 forming aggregates and playing a key role in the pathogenesis of
Huntington disease.
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