Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
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 ISI Web of Science
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 arrow Search for citing articles in:
ISI Web of Science (40)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Wheeler, V. C.
Right arrow Articles by MacDonald, M. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wheeler, V. C.
Right arrow Articles by MacDonald, M. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2002, Vol. 11, No. 6 633-640
© 2002 Oxford University Press

Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice

Vanessa C. Wheeler, Claire-Anne Gutekunst2, Vladimir Vrbanac, Lori-Anne Lebel, Gabriele Schilling4, Steven Hersch2, Robert M. Friedlander3, James F. Gusella, Jean-Paul Vonsattel1, David R. Borchelt4 and Marcy E. MacDonald+

Molecular Neurogenetics Unit and 1Molecular Neuropathology, Massachusetts General Hospital, Charlestown, MA 02129, USA, 2Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA, 3Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA and 4Department of Pathology, Johns Hopkins University, Baltimore, MD 21205-2196, USA

In Huntington’s disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include the formation of insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions and filter-trap amyloid, which may either participate in the disease process or be a degradative by-product. In young Hdh knock-in mice, CAGs that expand the glutamine tract in mouse huntingtin to childhood-onset HD lengths lead to nuclear accumulation of full-length mutant huntingtin and later accumulation of insoluble fragment. Here we report late-onset neurodegeneration and gait deficits in older HdhQ111 knock-in mice, demonstrating that the nuclear phenotypes comprise early stages in a disease process that conforms to genetic and pathologic criteria determined in HD patients. Furthermore, using the early nuclear-accumulation phenotypes as surrogate markers, we show in genetic experiments that the disease process, initiated by full-length mutant protein, is hastened by co-expression of mutant fragment; therefore, accrual of insoluble-product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by normal huntingtin or by mutant caspase-1, two proteins shown to reduce inclusions and glutamine toxicity in other HD models. Thus, potential HD therapies in man might be directed at different levels: preventing the disease-initiating mechanism or slowing the subsequent progression of pathogenesis.

+ To whom correspondence should be addressed. Tel: +1 617 726 5089; Fax: +1 617 726 5735; Email: macdonam@helix.mgh.harvard.edu Present address:Steven Hersch, Department of Neurology, Massachusetts General Hospital, Boston MA 02114, USA


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
M. Gray, D. I. Shirasaki, C. Cepeda, V. M. Andre, B. Wilburn, X.-H. Lu, J. Tao, I. Yamazaki, S.-H. Li, Y. E. Sun, et al.
Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice
J. Neurosci., June 11, 2008; 28(24): 6182 - 6195.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Lloret, E. Dragileva, A. Teed, J. Espinola, E. Fossale, T. Gillis, E. Lopez, R. H. Myers, M. E. MacDonald, and V. C. Wheeler
Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice
Hum. Mol. Genet., June 15, 2006; 15(12): 2015 - 2024.
[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
 Proc. Natl. Acad. Sci. USAHome page
S. Q. Harper, P. D. Staber, X. He, S. L. Eliason, I. H. Martins, Q. Mao, L. Yang, R. M. Kotin, H. L. Paulson, and B. L. Davidson
From the Cover: RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model
PNAS, April 19, 2005; 102(16): 5820 - 5825.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
C. M. Everett and N. W. Wood
Trinucleotide repeats and neurodegenerative disease
Brain, November 1, 2004; 127(11): 2385 - 2405.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
Q. Ruan, M. Lesort, M. E. MacDonald, and G. V.W. Johnson
Striatal cells from mutant huntingtin knock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway
Hum. Mol. Genet., April 1, 2004; 13(7): 669 - 681.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Gines, E. Ivanova, I.-S. Seong, C. A. Saura, and M. E. MacDonald
Enhanced Akt Signaling Is an Early Pro-survival Response That Reflects N-Methyl-D-aspartate Receptor Activation in Huntington's Disease Knock-in Striatal Cells
J. Biol. Chem., December 12, 2003; 278(50): 50514 - 50522.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
M. E. MacDonald
Huntingtin: Alive and Well and Working in Middle Management
Sci. Signal., November 4, 2003; 2003(207): pe48 - pe48.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
E. J. Slow, J. van Raamsdonk, D. Rogers, S. H. Coleman, R. K. Graham, Y. Deng, R. Oh, N. Bissada, S. M. Hossain, Y.-Z. Yang, et al.
Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease
Hum. Mol. Genet., July 1, 2003; 12(13): 1555 - 1567.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Xia, D. H. Lee, J. Taylor, M. Vandelft, and R. Truant
Huntingtin contains a highly conserved nuclear export signal
Hum. Mol. Genet., June 15, 2003; 12(12): 1393 - 1403.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Gines, I. S. Seong, E. Fossale, E. Ivanova, F. Trettel, J. F. Gusella, V. C. Wheeler, F. Persichetti, and M. E. MacDonald
Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice
Hum. Mol. Genet., March 1, 2003; 12(5): 497 - 508.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
V. C. Wheeler, L.-A. Lebel, V. Vrbanac, A. Teed, H. te Riele, and M. E. MacDonald
Mismatch repair gene Msh2 modifies the timing of early disease in HdhQ111 striatum
Hum. Mol. Genet., February 1, 2003; 12(3): 273 - 281.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
E. Fossale, V. C. Wheeler, V. Vrbanac, L.-A. Lebel, A. Teed, J. S. Mysore, J. F. Gusella, M. E. MacDonald, and F. Persichetti
Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice
Hum. Mol. Genet., September 15, 2002; 11(19): 2233 - 2241.
[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.