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.
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.
|Zhang, Jian; Li, Xiaoling; Kwansa, Herman et al. (2017) Augmentation of poly(ADP-ribose) polymerase-dependent neuronal cell death by acidosis. J Cereb Blood Flow Metab 37:1982-1993|
|Puschmann, Andreas; Fiesel, Fabienne C; Caulfield, Thomas R et al. (2017) Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain 140:98-117|
|Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S et al. (2017) Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and ?-Synuclein Pathology. eNeuro 4:|
|Sulzer, David; Alcalay, Roy N; Garretti, Francesca et al. (2017) T cells from patients with Parkinson's disease recognize ?-synuclein peptides. Nature 546:656-661|
|Liddelow, Shane A; Guttenplan, Kevin A; Clarke, Laura E et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481-487|
|Xiong, Yulan; Dawson, Ted M; Dawson, Valina L (2017) Models of LRRK2-Associated Parkinson's Disease. Adv Neurobiol 14:163-191|
|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|
|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|
|Lee, Yunjong; Stevens, Daniel A; Kang, Sung-Ung et al. (2017) PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. Cell Rep 18:918-932|
|Puschmann, Andreas; Fiesel, Fabienne C; Caulfield, Thomas R et al. (2017) Reply: Heterozygous PINK1 p.G411S in rapid eye movement sleep behaviour disorder. Brain 140:e33|
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