The influence of huntingtin protein size on nuclear localization and cellular toxicity

Abigail S. Hackam, Roshni Singaraja, Cheryl L. Wellington, Martina Metzler, Krista McCutcheon, Taiqi Zhang, Michael Kalchman, Michael R. Hayden

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1097-1105
Number of pages9
JournalJournal of Cell Biology
Volume141
Issue number5
DOIs
StatePublished - Jun 1 1998

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Hackam, A. S., Singaraja, R., Wellington, C. L., Metzler, M., McCutcheon, K., Zhang, T., Kalchman, M., & Hayden, M. R. (1998). The influence of huntingtin protein size on nuclear localization and cellular toxicity. Journal of Cell Biology, 141(5), 1097-1105. https://doi.org/10.1083/jcb.141.5.1097