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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-MDCN-A (91))
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Bosetti, Francesca
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Johns Hopkins University
Schools of Medicine
United States
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Kam, Tae-In; Mao, Xiaobo; Park, Hyejin et al. (2018) Poly(ADP-ribose) drives pathologic ?-synuclein neurodegeneration in Parkinson's disease. Science 362:
Hinkle, Jared T; Perepezko, Kate; Bakker, Catherine C et al. (2018) Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis. Int J Geriatr Psychiatry 33:e131-e139
Hinkle, Jared T; Perepezko, Kate; Mills, Kelly A et al. (2018) Dopamine transporter availability reflects gastrointestinal dysautonomia in early Parkinson disease. Parkinsonism Relat Disord 55:8-14
Hinkle, Jared T; Perepezko, Kate; Rosenthal, Liana S et al. (2018) Markers of impaired motor and cognitive volition in Parkinson's disease: Correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias. Parkinsonism Relat Disord 47:50-56
Berger, Nathan A; Besson, Valerie C; Boulares, A Hamid et al. (2018) Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases. Br J Pharmacol 175:192-222
Scott, Laura; Dawson, Valina L; Dawson, Ted M (2017) Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes. Exp Neurol 298:191-201
Ando, Maya; Fiesel, Fabienne C; Hudec, Roman et al. (2017) The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity. Mol Neurodegener 12:32
Ahrens-Nicklas, Rebecca C; Umanah, George K E; Sondheimer, Neal et al. (2017) Precision therapy for a new disorder of AMPA receptor recycling due to mutations inATAD1. Neurol Genet 3:e130
Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286
Fan, Jing; Dawson, Ted M; Dawson, Valina L (2017) Cell Death Mechanisms of Neurodegeneration. Adv Neurobiol 15:403-425

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