The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity

doi:10.1083/jcb.141.5.1097

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© The Rockefeller University Press, 0021-9525/1998//1097 $5.00
The Journal of Cell Biology, Volume 141, Number 5, , 1998 1097-1105

Articles

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, and Michael R. Hayden

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 neurodegenerativedisorder caused by the pathological expansion of a polyglutaminetract. In this study we directly assess the influence of proteinsize on the formation and subcellular localization of huntingtinaggregates. We have created numerous deletion constructs expressingsuccessively smaller fragments of huntingtin and show thatthese smaller proteins containing 128 glutamines form both intranuclearand perinuclear aggregates. In contrast, larger NH₂-terminal fragments of huntingtin proteins with 128 glutamines formexclusively perinuclear aggregates. These aggregates can formin the absence of endogenous huntingtin. Furthermore, expressionof mutant huntingtin results in increased susceptibility toapoptotic stress that is greater with decreasing protein lengthand increasing polyglutamine size. As both intranuclear andperinuclear aggregates are clearly associated with increased cellular toxicity, this supports an important role for toxicpolyglutamine-containing fragments forming aggregates and playinga key role in the pathogenesis of Huntington disease.

Abbreviations used in this paper: ES, embryonic stem; HD, Huntington disease; HEK, human embryonic kidney.

Address all correspondence to Dr. M.R. Hayden, Department ofMedical Genetics, University of British Columbia, 416-2125East Mall, NCE Bldg., Vancouver, BC V6T 1Z4. Tel.: (604) 822-9240.Fax: (604) 822-9238. E-mail: mrh{at}ulam.generes.ca

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