 |
 Previous Article | Next Article 
The Journal of Neuroscience, October 15, 2002, 22(20):8942-8950
Therapeutic Effects of Cystamine in a Murine Model of
Huntington's Disease
Alpaslan
Dedeoglu1, 2,
James K.
Kubilus1, 2,
Thomas
M.
Jeitner2, 4,
Samantha A.
Matson2,
Misha
Bogdanov3, 5,
Neil W.
Kowall1, 2,
Wayne R.
Matson3,
Arthur J. L.
Cooper4, 5, 6,
Rajiv R.
Ratan7,
M. Flint
Beal5, *,
Steven M.
Hersch8, *, and
Robert J.
Ferrante1, 2
1 Geriatric Research Education and Clinical Center,
Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, 2 Neurology, Pathology, and Psychiatry Departments, Boston
University School of Medicine, Boston, Massachusetts 02118, 3 ESA Laboratories, Inc., Chelmsford, Massachusetts 01824, Departments of 4 Biochemistry and 5 Neurology
and Neuroscience, Weill Medical College of Cornell University,
Presbyterian Hospital, New York, New York 10021, 6 Burke
Medical Research Institute, White Plains, New York 10605, 7 Department of Neurology and Program in Neuroscience,
Harvard Medical School and The Beth Israel-Deaconess Medical Center,
Boston, Massachusetts 02115, and 8 Center for Aging,
Genetics, and Neurodegeneration, Neurology Service, Massachusetts
General Hospital and Harvard Medical School, Boston, Massachusetts
02129
The precise cause of neuronal death in Huntington's disease (HD)
is unknown. Proteolytic products of the huntingtin protein can
contribute to toxic cellular aggregates that may be formed in part by
tissue transglutaminase (Tgase). Tgase activity is increased in HD
brain. Treatment in R6/2 transgenic HD mice, using the transglutaminase
inhibitor cystamine, significantly extended survival, improved body
weight and motor performance, and delayed the neuropathological
sequela. Tgase activity and N -(
-L-glutamyl)-L-lysine (GGEL) levels
were significantly altered in HD mice. Free GGEL, a specific
biochemical marker of Tgase activity, was markedly elevated in the
neocortex and caudate nucleus in HD patients. Both Tgase and GGEL
immunoreactivities colocalized to huntingtin aggregates. Cystamine
treatment normalized transglutaminase and GGEL levels in R6/2 mice.
These findings are consistent with the hypothesis that transglutaminase
activity may play a role in the pathogenesis of HD, and they identify
cystamine as a potential therapeutic strategy for treating HD patients.
Key words:
Huntington's disease; cystamine; transglutaminase; glutamyl lysine; neuroprotection; transgenic R6/2 mice
*
M.F.B. and S.M.H. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22208942-09$05.00/0
This article has been cited by other articles:
|
|
|
|
 
J. Shao, W. J. Welch, N. A. DiProspero, and M. I. Diamond
Phosphorylation of Profilin by ROCK1 Regulates Polyglutamine Aggregation
Mol. Cell. Biol.,
September 1, 2008;
28(17):
5196 - 5208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. A. Johnson, W. Yao, N. E. Lane, P. Naquet, and R. A. Terkeltaub
Vanin-1 Pantetheinase Drives Increased Chondrogenic Potential of Mesenchymal Precursors in ank/ank Mice
Am. J. Pathol.,
February 1, 2008;
172(2):
440 - 453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Chopra, J. H. Fox, G. Lieberman, K. Dorsey, W. Matson, P. Waldmeier, D. E. Housman, A. Kazantsev, A. B. Young, and S. Hersch
A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse
PNAS,
October 16, 2007;
104(42):
16685 - 16689.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Dominy Jr, C. R. Simmons, L. L. Hirschberger, J. Hwang, R. M. Coloso, and M. H. Stipanuk
Discovery and Characterization of a Second Mammalian Thiol Dioxygenase, Cysteamine Dioxygenase
J. Biol. Chem.,
August 31, 2007;
282(35):
25189 - 25198.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Ryu, J. Lee, S. W. Hagerty, B. Y. Soh, S. E. McAlpin, K. A. Cormier, K. M. Smith, and R. J. Ferrante
ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease
PNAS,
December 12, 2006;
103(50):
19176 - 19181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Antonyak, J. M. Jansen, A. M. Miller, T. K. Ly, M. Endo, and R. A. Cerione
Two isoforms of tissue transglutaminase mediate opposing cellular fates
PNAS,
December 5, 2006;
103(49):
18609 - 18614.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Duenas, R. Goold, and P. Giunti
Molecular pathogenesis of spinocerebellar ataxias
Brain,
June 1, 2006;
129(6):
1357 - 1370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Agrawal, J. Pallos, N. Slepko, B. L. Apostol, L. Bodai, L.-W. Chang, A.-S. Chiang, L. M. Thompson, and J. L. Marsh
Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila
PNAS,
March 8, 2005;
102(10):
3777 - 3781.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Halverson, J. Lewis, S. Frausto, M. Hutton, and N. A. Muma
Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice
J. Neurosci.,
February 2, 2005;
25(5):
1226 - 1233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Gardian, S. E. Browne, D.-K. Choi, P. Klivenyi, J. Gregorio, J. K. Kubilus, H. Ryu, B. Langley, R. R. Ratan, R. J. Ferrante, et al.
Neuroprotective Effects of Phenylbutyrate in the N171-82Q Transgenic Mouse Model of Huntington's Disease
J. Biol. Chem.,
January 7, 2005;
280(1):
556 - 563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lee, Y.-S. Kim, D.-H. Choi, M. S. Bang, T. R. Han, T. H. Joh, and S.-Y. Kim
Transglutaminase 2 Induces Nuclear Factor-{kappa}B Activation via a Novel Pathway in BV-2 Microglia
J. Biol. Chem.,
December 17, 2004;
279(51):
53725 - 53735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. Zainelli, C. A. Ross, J. C. Troncoso, J. K. Fitzgerald, and N. A. Muma
Calmodulin Regulates Transglutaminase 2 Cross-Linking of Huntingtin
J. Neurosci.,
February 25, 2004;
24(8):
1954 - 1961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Ferrante, J. K. Kubilus, J. Lee, H. Ryu, A. Beesen, B. Zucker, K. Smith, N. W. Kowall, R. R. Ratan, R. Luthi-Carter, et al.
Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice
J. Neurosci.,
October 15, 2003;
23(28):
9418 - 9427.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Marsh, J. Pallos, and L. M. Thompson
Fly models of Huntington's disease
Hum. Mol. Genet.,
October 15, 2003;
12(90002):
R187 - 193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. S. Roberts, M. A. Zandonatti, D. D. Watry, L. J. Madden, S. J. Henriksen, M. A. Taffe, and H. S. Fox
Induction of Pathogenic Sets of Genes in Macrophages and Neurons in NeuroAIDS
Am. J. Pathol.,
June 1, 2003;
162(6):
2041 - 2057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Apostol, A. Kazantsev, S. Raffioni, K. Illes, J. Pallos, L. Bodai, N. Slepko, J. E. Bear, F. B. Gertler, S. Hersch, et al.
A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila
PNAS,
May 13, 2003;
100(10):
5950 - 5955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Iuchi, G. Hoffner, P. Verbeke, P. Djian, and H. Green
Oligomeric and polymeric aggregates formed by proteins containing expanded polyglutamine
PNAS,
March 4, 2003;
100(5):
2409 - 2414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Junn, R. D. Ronchetti, M. M. Quezado, S.-Y. Kim, and M. M. Mouradian
Tissue transglutaminase-induced aggregation of alpha -synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies
PNAS,
February 18, 2003;
100(4):
2047 - 2052.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
