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19427306
Calcium dysregulation induces apoptosis-inducing factor release: cross-talk between PARP-1- and calpain-signaling pathways.

Exp Neurol, 2009/8;218(2):213-20.

Vosler PS[1], Sun D, Wang S, Gao Y, Kintner DB, Signore AP, Cao G, Chen J

Affiliations

PMID: 19427306DOI: 10.1016/j.expneurol.2009.04.032

Impact factor: 5.62

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 Ca(2+) dysregulation in a PARP-1 dependent manner. Thus, PARP-1 and mitochondrial calpain activation are linked via PARP-1-induced alterations in mitochondrial Ca(2+) homeostasis. Collectively, these findings link the two seemingly independent mechanisms triggering AIF-induced neuronal death.
MeSH terms
Analysis of Variance; Animals; Apoptosis; Apoptosis Inducing Factor; Blotting, Western; Calcium; Calpain; Cells, Cultured; Cerebral Cortex; DNA, Complementary; Excitatory Amino Acid Agonists; Genetic Vectors; Green Fluorescent Proteins; Mitochondria; N-Methylaspartate; Neurons; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; RNA, Small Interfering; Rats; Rats, Sprague-Dawley; Signal Transduction; Transfection
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