Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons

M. Mori, D. L. Burgess, L. A. Gefrides, P. J. Foreman, J. T. Opferman, S. J. Korsmeyer, E. A. Cavalheiro, Md G. Naffah-Mazzacoratti, J. L. Noebels

Research output: Contribution to journalArticlepeer-review

Abstract

Mcl1 is a Bcl2-related antiapoptotic protein originally isolated from human myelold leukemia cells. Unlike Bcl2, expression has not been reported in CNS neurons. We isolated Mcl1 in a direct screen for candidate modifier genes of neuronal vulnerability by differential display of mRNAs upregulated following prolonged seizures in two mouse strains with contrasting levels of hippocampal cell death. Mcl1 is widely expressed in neurons, and transcription is rapidly induced in both strains. In resistant C57BI/6J mice, Mcl1 protein levels remain persistently elevated in hippocampal pyramidal neurons after seizures, but fall rapidly in C3H/HeJ hippocampus, coinciding with extensive neuronal apoptosis. DNA damage and caspase-mediated cell death were strikingly increased in Mcl1-deficient mice when compared to +/+ littermates after similar seizures. We identify Mcl1 as a neuronal gene responsive to excitotoxic insult in the brain, and link relative levels of Mcl1 expression to inherited differences in neuronal thresholds for apoptosis.

Original languageEnglish (US)
Pages (from-to)1223-1233
Number of pages11
JournalCell death and differentiation
Volume11
Issue number11
DOIs
StatePublished - Nov 2004
Externally publishedYes

Keywords

  • Genetics
  • Hippocampus
  • Mcl1
  • Modifier genes
  • Neuronal cell death
  • Neuroprotection
  • Seizure

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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