Wild-type huntingtin protects from apoptosis upstream of caspase-3

J Neurosci. 2000 May 15;20(10):3705-13. doi: 10.1523/JNEUROSCI.20-10-03705.2000.


Expansion of a polyglutamine sequence in the N terminus of huntingtin is the gain-of-function event that causes Huntington's disease. This mutation affects primarily the medium-size spiny neurons of the striatum. Huntingtin is expressed in many neuronal and non-neuronal cell types, implying a more general function for the wild-type protein. Here we report that wild-type huntingtin acts by protecting CNS cells from a variety of apoptotic stimuli, including serum withdrawal, death receptors, and pro-apoptotic Bcl-2 homologs. This protection may take place at the level of caspase-9 activation. The full-length protein also modulates the toxicity of the poly-Q expansion. Cells expressing full-length mutant protein are susceptible to fewer death stimuli than cells expressing truncated mutant huntingtin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line, Transformed
  • Cell Survival / physiology
  • Cerebral Cortex / cytology
  • Corpus Striatum / cytology
  • Gene Expression Regulation, Enzymologic
  • In Situ Nick-End Labeling
  • Mutagenesis / physiology
  • Nerve Tissue Proteins / genetics*
  • Neurons / chemistry
  • Neurons / cytology*
  • Neurons / enzymology*
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic / physiology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Transfection
  • bcl-X Protein


  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Caspase 3
  • Caspase 9
  • Caspases