Caspase-8 is required for cell death induced by expanded polyglutamine repeats.
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.
Sánchez
I
I
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Xu
C J
CJ
Juo
P
P
Kakizaka
A
A
Blenis
J
J
Yuan
J
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000096:biosynthesis / Q000378:metabolism; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010455:Peptides / Q000502:physiology*; D010957:Plasmids; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D020449:Repetitive Sequences, Amino Acid; D015843:Serpins / Q000096:biosynthesis / Q000378:metabolism; D014764:Viral Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C505533:FADD protein, human; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D014764:Viral Proteins; C097188:polyglutamine; C074641:interleukin-1beta-converting enzyme inhibitor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases