Abstract
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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Acknowledgements
We thank H.Y. Zoghbi for providing SCA-1 lymphoblasts, and M. McInnis for providing control lymphoblasts. We thank S. Gartner for providing her facility. We thank C. Callahan, L. Hanle, X. Luo, A. McCall, M. Delanoy for their technical assistance. We thank J. Ha, G. Thinakaran and C.D. Ferris for discussions. We thank all the members of S.H.S. and C.A.R. labs for scientific support. We also thank D. Dodson, A. Kodaira, I. Yamamoto for typing and statistical analysis. This paper was supported by USPHS grant MH-18501 and Research Scientist Award DA-00074 to S.H.S.; NS16375 from NIH and HDSA "Coalition for the Cure" to C.A.R.; and a research grant from the Brain Science Foundation (Japan) to A.S.
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Sawa, A., Wiegand, G., Cooper, J. et al. Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med 5, 1194–1198 (1999). https://doi.org/10.1038/13518
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DOI: https://doi.org/10.1038/13518
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