Skip Navigation



Human Molecular Genetics Advance Access published online on June 9, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh175
© 2004 by Oxford University Press
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
13/15/1599    most recent
ddh175v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Schilling, G.
Right arrow Articles by Borchelt, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schilling, G.
Right arrow Articles by Borchelt, D. R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Article

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

Gabriele Schilling 1*, Alena V. Savonenko 2, Alexandra Klevytska 2, Johanna L. Morton 2, Stina M. Tucker 2, Michelle Poirier 3, Alexa Gale 2, Ning Chan 2, Vicky Gonzales 2, Hilda H. Slunt 2, Michael L. Coonfield 2, Nancy A. Jenkins 4, Neal G. Copeland 4, Christopher A. Ross 5, David R. Borchelt 6

1 Departments of Pathology, The Johns Hopkins University School of Medicine, Ross Building 558, 720 Rutland Ave., Baltimore MD 21205-2196
2 Departments of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205
3 Departments of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205
4 Departments of Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702
5 Departments of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205; Departments of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205
6 Departments of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205; Departments of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205

* To whom correspondence should be addressed. E-mail: gschill1{at}jhmi.edu.


  Abstract

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 CNS of patients have been found to accumulate N-terminal fragments of mutant huntingtin in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 aa of htt with 82 glutamines along with losses of motoric function, hypoactivity, and abbreviated life-span. The relative contributions of nuclear vs. cytoplasmic mutant huntingtin 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) were identified that expressed NLS-N171-82Q at comparable levels and which developed phenotypes identical to our previously described HD-N171-82Q mice. Western blot and immuno-histochemical analyses revealed 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Neurosci.Home page
A. L. Southwell, J. Ko, and P. H. Patterson
Intrabody Gene Therapy Ameliorates Motor, Cognitive, and Neuropathological Symptoms in Multiple Mouse Models of Huntington's Disease
J. Neurosci., October 28, 2009; 29(43): 13589 - 13602.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. K. Chaturvedi, P. Adhihetty, S. Shukla, T. Hennessy, N. Calingasan, L. Yang, A. Starkov, M. Kiaei, M. Cannella, J. Sassone, et al.
Impaired PGC-1{alpha} function in muscle in Huntington's disease
Hum. Mol. Genet., August 15, 2009; 18(16): 3048 - 3065.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. L. Benn, T. Sun, G. Sadri-Vakili, K. N. McFarland, D. P. DiRocco, G. J. Yohrling, T. W. Clark, B. Bouzou, and J.-H. J. Cha
Huntingtin Modulates Transcription, Occupies Gene Promoters In Vivo, and Binds Directly to DNA in a Polyglutamine-Dependent Manner
J. Neurosci., October 15, 2008; 28(42): 10720 - 10733.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
A. L. Southwell, A. Khoshnan, D. E. Dunn, C. W. Bugg, D. C. Lo, and P. H. Patterson
Intrabodies Binding the Proline-Rich Domains of Mutant Huntingtin Increase Its Turnover and Reduce Neurotoxicity
J. Neurosci., September 3, 2008; 28(36): 9013 - 9020.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. C. Warby, C. N. Doty, R. K. Graham, J. B. Carroll, Y.-Z. Yang, R. R. Singaraja, C. M. Overall, and M. R. Hayden
Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus
Hum. Mol. Genet., August 1, 2008; 17(15): 2390 - 2404.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Doi, K. Okamura, P. O. Bauer, Y. Furukawa, H. Shimizu, M. Kurosawa, Y. Machida, H. Miyazaki, K. Mitsui, Y. Kuroiwa, et al.
RNA-binding Protein TLS Is a Major Nuclear Aggregate-interacting Protein in Huntingtin Exon 1 with Expanded Polyglutamine-expressing Cells
J. Biol. Chem., March 7, 2008; 283(10): 6489 - 6500.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
I. Palazzolo, B. G. Burnett, J. E. Young, P. L. Brenne, A. R. La Spada, K. H. Fischbeck, B. W. Howell, and M. Pennuto
Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity
Hum. Mol. Genet., July 1, 2007; 16(13): 1593 - 1603.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
E. Rockabrand, N. Slepko, A. Pantalone, V. N. Nukala, A. Kazantsev, J. L. Marsh, P. G. Sullivan, J. S. Steffan, S. L. Sensi, and L. M. Thompson
The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis
Hum. Mol. Genet., January 1, 2007; 16(1): 61 - 77.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Cornett, L. Smith, M. Friedman, J.-Y. Shin, X.-J. Li, and S.-H. Li
Context-dependent Dysregulation of Transcription by Mutant Huntingtin
J. Biol. Chem., November 24, 2006; 281(47): 36198 - 36204.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
M. Arango, S. Holbert, D. Zala, E. Brouillet, J. Pearson, E. Regulier, A. K. Thakur, P. Aebischer, R. Wetzel, N. Deglon, et al.
CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity.
J. Neurosci., April 26, 2006; 26(17): 4649 - 4659.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
T. W. Sedlak and S. H. Snyder
Messenger Molecules and Cell Death: Therapeutic Implications
JAMA, January 4, 2006; 295(1): 81 - 89.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. L. Benn, C. Landles, H. Li, A. D. Strand, B. Woodman, K. Sathasivam, S.-H. Li, S. Ghazi-Noori, E. Hockly, S. M.N.N. Faruque, et al.
Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease
Hum. Mol. Genet., October 15, 2005; 14(20): 3065 - 3078.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. Iwata, J. C. Christianson, M. Bucci, L. M. Ellerby, N. Nukina, L. S. Forno, and R. R. Kopito
Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation
PNAS, September 13, 2005; 102(37): 13135 - 13140.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.