Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing

J Biol Chem. 2001 May 4;276(18):14545-8. doi: 10.1074/jbc.C100044200. Epub 2001 Mar 5.


Huntington's Disease is an inherited neurodegenerative disease that affects the medium spiny neurons in the striatum. The disease is caused by the expansion of a polyglutamine sequence in the N terminus of Huntingtin (Htt), a widely expressed protein. Recently, we have found that Htt is an antiapoptotic protein in striatal cells and acts by preventing caspase-3 activity. Here we report that Htt overexpression in other CNS-derived cells can protect them from more than 20 days exposure to fatal stimuli. In particular, we found that cytochrome c continues to be released from mitochondria into the cytosol of cells that overexpress normal Htt. However, procaspase-9 is not processed, indicating that wild-type Htt (wtHtt) acts downstream of cytochrome c release. These data show that Htt inhibits neuronal cell death by interfering with the activity of the apoptosome complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Caspase 9
  • Caspase Inhibitors*
  • Caspases / metabolism
  • Cell Line, Transformed
  • Cytochrome c Group / metabolism
  • Enzyme Activation
  • Enzyme Precursors / antagonists & inhibitors*
  • Enzyme Precursors / metabolism
  • Humans
  • Huntingtin Protein
  • Mitochondria / enzymology
  • Nerve Tissue Proteins / physiology*
  • Nuclear Proteins / physiology*


  • Caspase Inhibitors
  • Cytochrome c Group
  • Enzyme Precursors
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • CASP9 protein, human
  • Caspase 9
  • Caspases