Stroke and other neurodegenerative disorders are a leading cause of death, disability and loss of quality of life. The importance of glutamate neurotoxicity in cerebral ischemia and neurodegenerative diseases is well documented. Both in vitro and in vivo administration of glutamate and its analogs effectively kill neurons via excitotoxic mechanisms. Poly(ADP-ribose) polymerase-1 (PARP-1) is pivotal in glutamate neurotoxicity and cerebral infarction. Prior studies indicate that NO, or peroxynitrite plays a prominent role in glutamate excitotoxicity and cerebral infarction. Amongst other responses NO, or peroxynitrite, can activate PARP-1, which leads to cell death through the formation of complex and branched poly(ADP-ribose) (PAR) polymer. Recently, apoptosis inducing factor (AIF) has been identified as key mediator of neurotoxicity triggered by glutamate, reactive oxygen species, DNA damage and PAR polymer. AIF resides in the mitochondria in normal healthy cells, but moves to the nucleus following a lethal stimulus in a PARP-1 dependent manner. Blocking AIF from entering the nucleus can spare cells from death. This form of cell death has recently been designated parthanatos to distinguish it from other types of cell death such as apoptosis, necrosis or autophagic death. Interference with each step of the parthanatic cascade has been shown to be neuroprotective in a variety of models. Once AIF enters the nucleus, large scale DNA fragmentation (chromatinolysis) occurs through poorly characterized mechanisms, which is likely to be the execution step in parthanatic cell death. Accordingly, experiments are proposed to identify and characterize the parthanatos AIF associated endonuclease-1 (PAAN-1) and to investigate the role of PAAN-1 in excitotoxic and stroke induced neuronal injury. The identification of AIF interactors and understanding the mechanisms of PAAN-1 in neuronal injury will lead to new methods to terminate the toxic actions of NO, PAR and AIF and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.

Public Health Relevance

Stroke and other neurodegenerative disorders are a leading cause of death, disability and loss of quality of life. The project objectives are to understand th mechanisms of PARP-1 and AIF induced cell death and the actions of parthanatos AIF associated endonuclease-1 (PAAN-1) in stroke in order to identify strategies to terminate the toxic actions of PARP-1 activation and AIF. These finding could offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37NS067525-06
Application #
8832361
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (91))
Program Officer
Bosetti, Francesca
Project Start
2009-12-01
Project End
2018-11-30
Budget Start
2015-02-01
Budget End
2015-11-30
Support Year
6
Fiscal Year
2015
Total Cost
$729,000
Indirect Cost
$279,000
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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