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Previous Article | Next Article
The Journal of Neuroscience, February 1, 1999, 19(3):964-973
Mutant Huntingtin Expression in Clonal Striatal Cells: Dissociation of Inclusion Formation and Neuronal Survival by Caspase Inhibition
Manho Kim1, H-S Lee1, Genevieve LaForet2, Charmian McIntyre1, Eileen J. Martin1, Patrick Chang1, Tae Wan Kim1, M. Williams3, P. H. Reddy3, Dan Tagle3, Frederick M. Boyce1, Lisa Won4, Alfred Heller4, Neil Aronin2, and Marian DiFiglia1 1 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, 2 Departments of Medicine and Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, 3 National Institutes of Health, Bethesda, Maryland, 20892, and 4 Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637
Neuronal intranuclear inclusions are found in the brains of patients with Huntington's disease and form from the polyglutamine-expanded N-terminal region of mutant huntingtin. To explore the properties of inclusions and their involvement in cell death, mouse clonal striatal cells were transiently transfected with truncated and full-length human wild-type and mutant huntingtin cDNAs. Both normal and mutant proteins localized in the cytoplasm, and infrequently, in dispersed and perinuclear vacuoles. Only mutant huntingtin formed nuclear and cytoplasmic inclusions, which increased with polyglutamine expansion and with time after transfection. Nuclear inclusions contained primarily cleaved N-terminal products, whereas cytoplasmic inclusions contained cleaved and larger intact proteins. Cells with wild-type or mutant protein had distinct apoptotic features (membrane blebbing, shrinkage, cellular fragmentation), but those with mutant huntingtin generated the most cell fragments (apoptotic bodies). The caspase inhibitor Z-VAD-FMK significantly increased cell survival but did not diminish nuclear and cytoplasmic inclusions. In contrast, Z-DEVD-FMK significantly reduced nuclear and cytoplasmic inclusions but did not increase survival. A series of N-terminal products was formed from truncated normal and mutant proteins and from full-length mutant huntingtin but not from full-length wild-type huntingtin. One prominent N-terminal product was blocked by Z-VAD-FMK. In summary, the formation of inclusions in clonal striatal cells corresponds to that seen in the HD brain and is separable from events that regulate cell death. N-terminal cleavage may be linked to mutant huntingtin's role in cell death.
Key words: NH2-terminal huntingtin fragments; nuclear inclusions; cytoplasmic inclusions; full-length huntingtin; apoptosis; apoptotic bodies; membrane blebbing; Z-VAD-FMK; Z-DEVD-FMK; striatal hybrid cells
Copyright © 1999 Society for Neuroscience 0270-6474/99/193964-10$05.00/0
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[Abstract] [Full Text] [PDF]
D. Rigamonti, J. H. Bauer, C. De-Fraja, L. Conti, S. Sipione, C. Sciorati, E. Clementi, A. Hackam, M. R. Hayden, Y. Li, et al.
Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3
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[Abstract] [Full Text] [PDF]
M. I. Diamond, M. R. Robinson, and K. R. Yamamoto
Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor
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[Abstract] [Full Text] [PDF]
Y. Chai, S. L. Koppenhafer, N. M. Bonini, and H. L. Paulson
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[Abstract] [Full Text] [PDF]
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[Abstract] [Full Text] [PDF]
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