[Frontiers in Bioscience 14, 1116-1128, January 1, 2009]

Parthanatos, a messenger of death

Karen Kate David1, Shaida Ahmad Andrabi2, Ted Murray Dawson3, Valina Lynn Dawson4

1Institute for Cell Engineering, The Johns Hopkins University School of Medicine, 733 North Broadway St., Suite 711, Baltimore, MD 21205, USA, 2Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, 733 North Broadway St., Suite 711, Baltimore, MD 21205, USA, 3Departments of Neurology, The Johns Hopkins University School of Medicine, 733 North Broadway St., Suite 711, Baltimore, MD 21205, USA,4Neuroscience Physiology, The Johns Hopkins University School of Medicine, 733 North Broadway St., Suite 711, Baltimore, MD 21205, USA

TABLE OF CONTENTS

1. Abstract
2. Background
2.1. PARP family
2.2. Synthesis of poly-(ADP) ribose
2.3. PARP-1 in life and death
3. PARP-1 is a regulator of cell death
3.1. PARP-1 and excitotoxicity
3.2. PARP-1 overactivation depletes NAD+
3.3. PARP-1 overactivation induces AIF release
4. Parthanatos, a messenger of death
4.1. PAR polymer is toxic
4.2 . Properties of parthanatos
4.3 . Insights from PARG (poly-(ADP) ribose glycohydrolase) deletion
4.4. Structural species of PAR and its functional relevance
4.5. PAR and mitochondria
5. Conclusion
6. Acknowledgements
7. References

1. ABSTRACT

Poly-ADP-ribose polymerase-1 (PARP-1)'s roles in the cell span from maintaining life to inducing death. The processes PARP-1 is involved in include DNA repair, DNA transcription, mitosis, and cell death. Of PARP-1's different cellular functions, its role in cell death is of particular interest to designing therapies for diseases. Genetic deletion of PARP-1 revealed that PARP-1 overactivation underlies cell death in models of stroke, diabetes, inflammation and neurodegeneration. Since interfering with PARP-1 mediated cell death will be clinically beneficial, great effort has been invested into understanding mechanisms downstream of PARP-1 overactivation. Recent evidence shows that poly-ADP ribose (PAR) polymer itself can act as a cell death effector downstream of PARP-1. We coined the term parthanatos after Thanatos, the personification of death in Greek mythology, to refer to PAR-mediated cell death. In this review, we will present evidence and questions raised by these recent findings, and summarize the proposed mechanisms by which PARP-1 overactivation kills. It is evident that further understanding of parthanatos opens up new avenues for therapy in ameliorating diseases related to PARP-1 overactivation.