Caspase-8 is required for cell death induced by expanded polyglutamine repeats

Neuron. 1999 Mar;22(3):623-33. doi: 10.1016/s0896-6273(00)80716-3.

Abstract

We show here that caspase-8 is required for the death of primary rat neurons induced by an expanded polyglutamine repeat (Q79). Expression of Q79 recruited and activated caspase-8. Inhibition of caspase-8 blocked polyglutamine-induced cell death. Coexpression of Q79 with the caspase inhibitor CrmA, a dominant-negative mutant of FADD (FADD DN), Bcl-2, or Bcl-xL, but not an N-terminally tagged Bcl-xL, prevented the recruitment of caspase-8 and inhibited polyglutamine-induced cell death. Furthermore, Western blot analysis revealed the presence of activated caspase-8 in the insoluble fraction of affected brain regions from Huntington's disease (HD) patients but not in those from neurologically unremarkable controls, suggesting the relocation and activation of caspase-8 during the pathogenesis of HD. These results suggest an essential role of caspase-8 in HD-related neural degenerative diseases.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis / physiology*
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / genetics
  • Caspases / physiology*
  • Cell Line
  • Cysteine Proteinase Inhibitors / biosynthesis
  • Cysteine Proteinase Inhibitors / metabolism
  • Enzyme Activation
  • Fas-Associated Death Domain Protein
  • Fluorescent Antibody Technique, Direct
  • Humans
  • Immunoblotting
  • Microscopy, Confocal
  • Mutation
  • Neurons / enzymology
  • Neurons / physiology*
  • Peptides / physiology*
  • Plasmids
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Repetitive Sequences, Amino Acid
  • Serpins / biosynthesis
  • Serpins / metabolism
  • Viral Proteins*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • FADD protein, human
  • Fadd protein, rat
  • Fas-Associated Death Domain Protein
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • Serpins
  • Viral Proteins
  • polyglutamine
  • interleukin-1beta-converting enzyme inhibitor
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp8 protein, rat
  • Casp9 protein, rat
  • Caspase 8
  • Caspase 9
  • Caspases