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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1 June 1998
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June 01 1998
The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity
Abigail S. Hackam,
Abigail S. Hackam
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
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Roshni Singaraja,
Roshni Singaraja
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
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Cheryl L. Wellington,
Cheryl L. Wellington
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
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Martina Metzler,
Martina Metzler
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
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Krista McCutcheon,
Krista McCutcheon
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
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Taiqi Zhang,
Taiqi Zhang
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
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Michael Kalchman,
Michael Kalchman
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
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Michael R. Hayden
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
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Abigail S. Hackam
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
Roshni Singaraja
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
Cheryl L. Wellington
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
Martina Metzler
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
Krista McCutcheon
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
Taiqi Zhang
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
Michael Kalchman
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
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
Address all correspondence to Dr. M.R. Hayden, Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Bldg., Vancouver, BC V6T 1Z4. Tel.: (604) 822-9240. Fax: (604) 822-9238. E-mail: [email protected]
Received:
March 03 1998
Revision Received:
April 23 1998
Online ISSN: 1540-8140
Print ISSN: 0021-9525
1998
J Cell Biol (1998) 141 (5): 1097–1105.
Article history
Received:
March 03 1998
Revision Received:
April 23 1998
Citation
Abigail S. Hackam, Roshni Singaraja, Cheryl L. Wellington, Martina Metzler, Krista McCutcheon, Taiqi Zhang, Michael Kalchman, Michael R. Hayden; The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity . J Cell Biol 1 June 1998; 141 (5): 1097–1105. doi: https://doi.org/10.1083/jcb.141.5.1097
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