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Cytochrome C and caspase-9 expression in Huntington’s disease

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Abstract

There is increasing evidence implicating apoptosis-mediated cell death in the pathogenesis of neurodegenerative diseases. One important event in the apoptotic cascade is the release of cytochrome c by mitochondria into the cytoplasm, activating caspase-9, leading to the subsequent activation of downstream executioner caspases. In the present study, we examined the distribution of cytochrome c and caspase-9 in Huntington’s disease (HD) patients and in a transgenic model of HD (R6/2 line). Neuronal cytochrome c immunoreactivity increased with neuropathological severity in HD patients. Concomitant with this finding, Western-blot analysis showed a shift in the distribution of cytochrome c from the mitochondrial to the cytosolic fraction with incremental cytosolic expression associated with greater striatal degeneration. Active caspase-9 immunoreactivity was present in both HD striatal neurons and in Western blots of severe-grade specimens. Similar findings were observed in the R6/2 mice. There was a temporal increase in expression and shift of cytochrome c from the mitochondrial to the cytosolic fraction from 4–13 wk of age. Activated caspase-9 and caspase 3 activities were present only at endstage disease. Although the present results provide evidence that key components of the intrinsic mitochondrial apoptotic pathway are activated in both HD patients and a transgene murine model of HD, these phenomena are prominent in only severe neuropathological grades in HD patients and HD mice, suggesting that apoptosis may play a greater role in neuronal death at endstage disease.

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Authors and Affiliations

  1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, MA

    Tamara Kiechle, Alpaslan Dedeoglu, James Kubilus, Neil W. Kowall & Robert J. Ferrante

  2. Neurology, Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, MA

    Tamara Kiechle, Alpaslan Dedeoglu, James Kubilus, Neil W. Kowall & Robert J. Ferrante

  3. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY

    Robert M. Friedlander

  4. Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA

    Robert M. Friedlander

  5. Center for Aging, Genetics and Neurodegenerative Diseases, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA

    M. Flint Beal & Steven M. Hersch

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  1. Tamara Kiechle
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  2. Alpaslan Dedeoglu
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  8. Robert J. Ferrante
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Correspondence to Robert J. Ferrante.

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Kiechle, T., Dedeoglu, A., Kubilus, J. et al. Cytochrome C and caspase-9 expression in Huntington’s disease. Neuromol Med 1, 183–195 (2002). https://doi.org/10.1385/NMM:1:3:183

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  • DOI: https://doi.org/10.1385/NMM:1:3:183

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