Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death

Nat Med. 2011 Jun;17(6):692-9. doi: 10.1038/nm.2387. Epub 2011 May 22.

Abstract

Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Inducing Factor / physiology
  • Blotting, Northern
  • Brain / physiology*
  • Calcium / metabolism
  • Cell Death / physiology
  • Glutamic Acid / drug effects
  • Glutamic Acid / physiology
  • Mice
  • Mitochondria / metabolism
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly Adenosine Diphosphate Ribose / antagonists & inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Poly(ADP-ribose) Polymerases / physiology
  • Protein Binding
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Stroke / physiopathology*

Substances

  • Apoptosis Inducing Factor
  • Nerve Tissue Proteins
  • Pdcd8 protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • Poly Adenosine Diphosphate Ribose
  • Glutamic Acid
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Calcium