Mutant Huntingtin expression in clonal striatal cells: Dissociation of inclusion formation and neuronal survival by caspase inhibition

Manho Kim, H. S. Lee, Genevieve LaForet, Charmian McIntyre, Eileen J. Martin, Patrick Chang, Tae Wan Kim, M. Williams, P. H. Reddy, Dan Tagle, Frederick M. Boyce, Lisa Won, Alfred Heller, Neil Aronin, Marian DiFiglia

Research output: Contribution to journalArticlepeer-review

257 Scopus citations


Neuronal intranuclear inclusions are found in the brains of patients with Huntington's disease and form from the polyglutamine-expanded N-terminal region of mutant huntingtin. To explore the properties of inclusions and their involvement in cell death, mouse clonal striatal cells were transiently transfected with truncated and full-length human wild-type and mutant huntingtin cDNAs. Both normal and mutant proteins localized in the cytoplasm, and infrequently, in dispersed and perinuclear vacuoles. Only mutant huntingtin formed nuclear and cytoplasmic inclusions, which increased with polyglutamine expansion and with time after transfection. Nuclear inclusions contained primarily cleaved N-terminal products, whereas cytoplasmic inclusions contained cleaved and larger intact proteins. Cells with wild- type or mutant protein had distinct apoptotic features (membrane blebbing, shrinkage, cellular fragmentation), but those with mutant huntingtin generated the most cell fragments (apoptotic bodies). The caspase inhibitor Z-VAD-FMK significantly increased cell survival but did not diminish nuclear and cytoplasmic inclusions. In cortrast, Z-DEVD-FMK significantly reduced nuclear and cytoplasmic inclusions but did not increase survival. A series of N-terminal products was formed from truncated normal and mutant proteins and from full-length mutant huntingtin but not from full-length wild-type huntingtin. One prominent N-terminal product was blocked by Z-VAD-FMK. In summary, the formation of inclusions in clonal striatal cells corresponds to that seen in the HD brain and is separable from events that regulate cell death. N-terminal cleavage may be linked to mutant huntingtin's role in cell death.

Original languageEnglish (US)
Pages (from-to)964-973
Number of pages10
JournalJournal of Neuroscience
Issue number3
StatePublished - Feb 1 1999
Externally publishedYes


  • Apoptosis
  • Apoptotic bodies
  • Cytoplasmic inclusions
  • Full-length huntingtin
  • Membrane blebbing
  • NH-terminal huntingtin fragments
  • Nuclear inclusions
  • Striatal hybrid cells

ASJC Scopus subject areas

  • Neuroscience(all)


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