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Human Molecular Genetics Advance Access originally published online on June 9, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 15 1599-1610
DOI: 10.1093/hmg/ddh175
Human Molecular Genetics, Vol. 13, No. 15 © Oxford University Press 2004; all rights reserved

Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice

Gabriele Schilling1,*, Alena V. Savonenko1, Alexandra Klevytska1, Johanna L. Morton1, Stina M. Tucker1, Michelle Poirier2, Alexa Gale1, Ning Chan1, Vicky Gonzales1, Hilda H. Slunt1, Michael L. Coonfield1, Nancy A. Jenkins4, Neal G. Copeland4, Christopher A. Ross2,3 and David R. Borchelt1,3

1Department of Pathology, 2Department of Psychiatry and Behavioral Sciences, 3Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 4Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA

Received March 24, 2004; Accepted May 26, 2004

Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to the pathogenesis of disease have not been clarified. To examine whether pathogenic processes in the nucleus disproportionately contribute to disease features in vivo, we fused a nuclear localization signal (NLS) derived from atrophin-1 to the N-terminus of an N171–82Q construct. Two lines of mice (lines 8A and 61) that were identified expressed NLS–N171–82Q at comparable levels and developed phenotypes identical to our previously described HD–N171–82Q mice. Western blot and immunohistochemical analyses revealed that NLS–N171–82Q fragments accumulate in nuclear, but not cytoplasmic, compartments. These data suggest that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of htt.

* To whom correspondence should be addressed at: Ross Building 558, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA. Tel: +1 4105025196; Fax: +1 4109559777; Email: gschill1{at}jhmi.edu


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