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Excitotoxic Programmed Cell Death Involves Caspase-Independent Mechanisms

  • Ted M. Dawson
  • Valina L. Dawson
Chapter

Abstract

Excitotoxicity is a common pathological process in many neurologic and neurodegenerative disorders, and this process involves over-stimulation of glutamate receptors and an excessive influx of calcium into cells. Cell death in excitotoxicity is unique in that, for the most part, it does not involve caspase-dependent pathways. Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) is an early pathological event in excitotoxicity that leads to a unique form of cell death called parthanatos. Biochemical events in parthanatos include early accumulation of poly (ADP-ribose) (PAR) and nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria followed by nuclear accumulation of macrophage migration inhibitory factor (MIF). MIF’s nuclease activity serves as the final executioner in excitotoxicity by shredding genomic DNA. Interfering with PARP activation, PAR signaling or MIF nuclease activity offers therapeutic interventions that could protect against a variety of neuronal injury due to a variety of insults involving glutamate excitotoxicity.

Keywords

Poly (ADP-ribose) polymerase-1 (PARP-1) Parthanatos Poly (ADP-ribose) (PAR) Apoptosis inducing factor (AIF) Macrophage migration inhibitory factor (MIF) Glutamate 

Notes

Acknowledgements

This work was supported by US National Institutes of Health grants NS38377, NS67525, and DA00266. The authors thank I-Hsun Wu for assistance with the illustrations. T. M. D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute for Cell EngineeringJohns Hopkins University School of MedicineBaltimoreUSA

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