Involvement of a caspase-3-like cysteine protease in 1-methyl-4- phenylpyridinium-mediated apoptosis of cultured cerebellar granule neurons

Yangshen Du, Richard C. Dodel, Kelly R. Bales, Ronald Jemmerson, Elizabeth Hamilton-Byrd, Steven M. Paul

Research output: Contribution to journalArticle

155 Scopus citations

Abstract

Exposure of various neuronal cells or cell lines to high concentrations of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), results in cell death. Recently, it has been reported that low concentrations of MPP+ induce apoptosis in susceptible neurons. We have further characterized MPP+-mediated toxicity of cultured cerebellar granule neurons (CGNs) and found that exposure of CGNs to relatively low concentrations of MPP+ results in apoptosis, whereas higher concentrations result in necrosis. Cotreatment of CGNs with MPP+ and the tetrapeptide inhibitor of caspase-3-like proteases, acetyl-DEVD-CHO, markedly attenuates apoptotic but not necrotic death of these neurons. The more specific inhibitor of caspase-l-like proteases, acetyl-YVAD-CHO, however, was ineffective against MPP+ neurotoxicity. Moreover, cytoplasmic extracts prepared from MPP+-treated CGNs contain markedly increased protease activity that cleaves the caspase-3 substrate acetyl-DEVD-p-nitroaniline. Finally, the cytoplasmic concentration of the apo-ptogenic protein cytochrome c was increased in a time-dependent fashion in MPP+-treated CGNs before the onset of apoptosis. Our data confirm that the neurotoxicity of MPP+ is due to both necrosis and apoptosis and suggest that the latter is mediated by activation of a caspase-3-like protease.

Original languageEnglish (US)
Pages (from-to)1382-1388
Number of pages7
JournalJournal of Neurochemistry
Volume69
Issue number4
StatePublished - Oct 1 1997

Keywords

  • Apoptosis
  • CPP32
  • Caspase- 3
  • Cell death
  • Cerebellar granule neurons
  • Cytochrome c
  • MPP
  • Mitochondria
  • Necrosis
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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