Nature Medicine
5, 1194 - 1198 (1999)
doi:10.1038/13518
Increased apoptosis of Huntington disease lymphoblasts associated with
repeat length-dependent mitochondrial depolarizationAkira Sawa1, Gordon W. Wiegand2, Jillian Cooper3, Russell L. Margolis3, Alan H. Sharp3, Joseph F. Lawler Jr.1, J. Timothy Greenamyre6, Solomon H. Snyder1, 3, 4, 5
& Christopher A. Ross1, 3, 51
Department of Neuroscience, Johns Hopkins University
School of Medicine, 725 N. Wolfe Street, Baltimore
, Maryland 21205, USA
2
Department of Medicine, Johns Hopkins University School
of Medicine, 725 N. Wolfe Street, Baltimore,
Maryland 21205, USA
3
Departments of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine, 725 N. Wolfe Street
, Baltimore, Maryland 21205,
USA
4
Departments of Pharmacology and Molecular Science,
Johns Hopkins University School of Medicine, 725 N. Wolfe Street
, Baltimore, Maryland 21205,
USA
5
Program in Cellular and Molecular Medicine, Johns Hopkins
University School of Medicine, 725 N. Wolfe Street,
Baltimore, Maryland 21205, USA
6
Department of Neurology, Emory University,
1639 Pierce Dr. WMB 6000, Atlanta, Georgia
30322, USA
7
G.W.B. present address: National Cancer Institute,
Frederick, Maryland
Correspondence should be addressed to Solomon H. Snyder Huntington disease (HD) is a genetically dominant condition caused by expanded
CAG repeats coding for glutamine in the HD gene product huntingtin1.
Although HD symptoms reflect preferential neuronal death in specific brain
regions, huntingtin is expressed in almost all tissues2, so
abnormalities outside the brain might be expected. Although involvement of
nuclei3,
4,
5,
6,
7 and mitochondria8,
9,
10,
11,
12,
13,
14
in HD pathophysiology has been suggested, specific intracellular defects that
might elicit cell death have been unclear. Mitochondria dysfunction is reported
in HD brains10,
11,
12,
13; mitochondria are organelles that
regulates apoptotic cell death15,
16. We now report that lymphoblasts
derived from HD patients showed increased stress-induced apoptotic cell death
associated with caspase-3 activation. When subjected to stress, HD lymphoblasts
also manifested a considerable increase in mitochondrial depolarization correlated
with increased glutamine repeats.
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