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  • The EMBO Journal (2006) 25, 5896 - 5906
  • doi:10.1038/sj.emboj.7601445

Published online: 23 November 2006

Huntingtin inhibits caspase-3 activation

Yu Zhang1, Blair R Leavitt2, Jeremy M van Raamsdonk2, Ioannis Dragatsis3, Dan Goldowitz4, Marcy E MacDonald5, Michael R Hayden2 and Robert M Friedlander1

  1. Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  2. Center for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, Children's & Women's Hospital, Vancouver, British Columbia, Canada
  3. Department of Physiology, Health Science Center, University of Tennessee, Memphis, TN, USA
  4. Department of Anatomy and Neurobiology, Health Science Center, University of Tennessee, Memphis, TN, USA
  5. Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Charlestown, MA, USA

Correspondence to:

Robert M Friedlander, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Tel.: +1 617 525 7775; Fax: +1 617 734 8342; E-mail: rfriedlander@rics.bwh.harvard.edu

Received 13 March 2006; Accepted 25 October 2006

Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild-type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase-3 activation, and overexpression of huntingtin resulted in caspase-3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase-3. Interestingly, mutant huntingtin binds active caspase-3 with a lower affinity and lower inhibitory effect on active caspase-3 than does wild-type huntingtin. Although reduction of huntingtin levels resulted in caspase-3 activation in all conditions examined, the cellular response was cell-type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase-3 activity, suggesting a mechanism whereby caspase-mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase-3 activation, resulting in cell dysfunction and cell death.

  • Keywords:

    • caspases-3,
    • huntingtin,
    • Huntington's disease