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

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

Research output: Contribution to journalArticle

154 Citations (Scopus)

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 1997

Fingerprint

1-Methyl-4-phenylpyridinium
Cysteine Proteases
Caspase 3
Neurons
Apoptosis
Peptide Hydrolases
Necrosis
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Caspase Inhibitors
Cell death
Metabolites
Cytochromes c
Toxicity
Cell Death
Chemical activation
Cells
Cell Line
Substrates

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Involvement of a caspase-3-like cysteine protease in 1-methyl-4- phenylpyridinium-mediated apoptosis of cultured cerebellar granule neurons. / Du, Yansheng; Dodel, Richard C.; Bales, Kelly R.; Jemmerson, Ronald; Hamilton-Byrd, Elizabeth; Paul, Steven M.

In: Journal of Neurochemistry, Vol. 69, No. 4, 10.1997, p. 1382-1388.

Research output: Contribution to journalArticle

Du, Yansheng ; Dodel, Richard C. ; Bales, Kelly R. ; Jemmerson, Ronald ; Hamilton-Byrd, Elizabeth ; Paul, Steven M. / Involvement of a caspase-3-like cysteine protease in 1-methyl-4- phenylpyridinium-mediated apoptosis of cultured cerebellar granule neurons. In: Journal of Neurochemistry. 1997 ; Vol. 69, No. 4. pp. 1382-1388.
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