Calcium dysregulation induces apoptosis-inducing factor release: Cross-talk between PARP-1- and calpain- signaling pathways

Peter Vosler, Dandan Sun, Suping Wang, Yanqin Gao, Douglas B. Kintner, Armando P. Signore, Guodong Cao, Jun Chen

Research output: Contribution to journalArticle

Abstract

Recent discoveries show that caspase-independent cell death pathways are a pervasive mechanism in neurodegenerative diseases, and apoptosis-inducing factor (AIF) is an important effector of this mode of neuronal death. There are currently two known mechanisms underlying AIF release following excitotoxic stress, PARP-1 and calpain. To test whether there is an interaction between PARP-1 and calpain in triggering AIF release, we used the NMDA toxicity model in rat primary cortical neurons. Exposure to NMDA resulted in AIF truncation and nuclear translocation, and shRNA-mediated knockdown of AIF resulted in neuroprotection. Both calpain and PARP-1 are involved with AIF processing as AIF truncation, nuclear translocation and neuronal death were attenuated by calpain inhibition using adeno-associated virus-mediated overexpression of the endogenous calpain inhibitor, calpastatin, or treatment with the PARP-1 inhibitor 3-ABA. Activation of PARP-1 is necessary for calpain activation as PARP-1 inhibition blocked mitochondrial calpain activation. Finally, NMDA toxicity induces mitochondrial Ca2+ dysregulation in a PARP-1 dependent manner. Thus, PARP-1 and mitochondrial calpain activation are linked via PARP-1-induced alterations in mitochondrial Ca2+ homeostasis. Collectively, these findings link the two seemingly independent mechanisms triggering AIF-induced neuronal death.

Original languageEnglish (US)
Pages (from-to)213-220
Number of pages8
JournalExperimental Neurology
Volume218
Issue number2
DOIs
Publication statusPublished - Aug 1 2009
Externally publishedYes

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Keywords

  • Apoptosis-inducing factor
  • Calcium homeostasis
  • Calpain
  • Ischemia
  • Mitochondria
  • NMDA toxicity
  • PARP-1

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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