Participation of Par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid

Wenzhen Duan, Zhihong Guo, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum is a major site of neuronal loss in HD, but the mechanisms underlying the neurodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rodents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate apoptosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, after systemic administration of 3NP to adult rats. The increase in Par-4 levels occurred within 6 h of 3NP administration and was followed by an increase in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels and caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activation, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppressed 3NP-induced apoptosis of striatal neurons, but did not prevent induction of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalExperimental Neurology
Issue number1
StatePublished - 2000
Externally publishedYes


  • 3-nitropropionic acid
  • Apoptosis
  • Caspase
  • Huntingtin
  • Huntington's disease
  • PARP
  • Trinucleotide

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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