Parthanatos, PAAN/MIF nuclease Activation in Ischemic Injury

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Project Summary/Abstract: 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. 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, necroptosis 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 the Parthanatos Associated AIF (apoptosis-inducing factor) Nuclease (PAAN) also known as MIF, where PAAN/MIF is a major mediator of parthanatic cell death in acute ischemic disorders via its nuclease activity. Recently, MIF has been suggested to be required for inflammasome activation. Accordingly, we propose to explore the use of a first in class, MIF nuclease inhibitor in stroke models and explore the contributions of PAAN/MIF’s nuclease activity in the activation of cGas and STING pathway and subsequent NLRP3 activation. We will also dissect the role of PAAN/MIF’s nuclease activity in neurons versus microglia in ischemic injury. Understanding the mechanisms of PAAN/MIF’s nuclease activity in neuronal injury will lead to innovative therapeutic approaches to treat neurodegenerative diseases and stroke.