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Human Molecular Genetics Advance Access originally published online on November 8, 2005
Human Molecular Genetics 2005 14(24):3823-3835; doi:10.1093/hmg/ddi407
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease

Jeremy M. Van Raamsdonk1,2, Zoe Murphy1,2, Elizabeth J. Slow1,2, Blair R. Leavitt1,2 and Michael R. Hayden1,2,*

1Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 and 2Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, Vancouver, BC, Canada V5Z 4H4

* To whom correspondence should be addressed at: Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, 980 West 28th Avenue, Vancouver, BC, Canada, V5Z 4H4. Email: mrh{at}cmmt.ubc.ca

Received August 13, 2005; Accepted October 21, 2005

Huntington disease (HD) is an adult onset neurodegenerative disorder that predominantly affects the striatum and cortex despite ubiquitous expression of mutant huntingtin (htt). Here we demonstrate that this pattern of selective degeneration is present in the YAC128 mouse model of HD. At 12 months, YAC128 mice show significant atrophy in the striatum, globus pallidus and cortex with relative sparing of the hippocampus and cerebellum (striatum: –10.4%, P<0.001; globus pallidus: –10.8%, P=0.04; cortex: –8.6%, P=0.001; hippocampus: +0.3%, P=0.9; cerebellum: +2.9%, P=0.6). Similarly, neuronal loss at this age is present in the striatum (–9.1%, P<0.001) and cortex of YAC128 mice (–8.3%, P=0.02) but is not detected in the hippocampus (+1.5%, P=0.72). Mutant htt expression levels are similar throughout the brain and fail to explain the selective neuronal degeneration. In contrast, nuclear detection of mutant htt occurs earliest and to the greatest extent in the striatum—the region most affected in HD. The appearance of EM48-reactive mutant htt in the nucleus in the striatum at 2 months coincides with the onset of behavioral abnormalities in YAC128 mice. In contrast to YAC128 mice, the R6/1 mouse model of HD, which expresses exon 1 of mutant htt, exhibits non-selective, widespread atrophy along with non-selective nuclear detection of mutant htt at 10 months of age. Our findings suggest that selective nuclear localization of mutant htt may contribute to the selective degeneration in HD and that appropriately regulated expression of full-length mutant htt in YAC128 mice results in a pattern of degeneration remarkably similar to human HD.


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