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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
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