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. The proteins and the mechanisms that are involved in facilitating the release of AIF from the mitochondria following PARP-1 activation are not known. Accordingly, experiments are proposed to elucidate the underlying molecular mechanisms accounting for AIF release following PARP-1 activation and to investigate the role of PAR polymer in excitotoxic and stroke induced neuronal injury. We hope that understanding the mechanisms of PAR polymer induced cell death, the activation of AIF and the identification of additional components of the PAR/AIF signaling complex will lead to new methods to terminate the toxic actions of PAR polymer 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. We hope that understanding the mechanisms of PAR polymer neurotoxic actions in stroke will lead to new methods to terminate the toxic actions of PAR polymer and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.
|Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102|
|Xu, Jin-Chong; Fan, Jing; Wang, Xueqing et al. (2016) Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med 8:333ra48|
|Lee, Jennifer K; Poretti, Andrea; Perin, Jamie et al. (2016) Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic-Ischemic Brain Injury. Dev Neurosci :|
|Scarffe, Leslie A; Stevens, Daniel A; Dawson, Valina L et al. (2014) Parkin and PINK1: much more than mitophagy. Trends Neurosci 37:315-24|
|Lee, Yun-Il; Giovinazzo, Daniel; Kang, Ho Chul et al. (2014) Protein microarray characterization of the S-nitrosoproteome. Mol Cell Proteomics 13:63-72|
|Fatokun, Amos A; Dawson, Valina L; Dawson, Ted M (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000-16|
|Pirooznia, Sheila K; Dawson, Valina L; Dawson, Ted M (2014) Motor neuron death in ALS: programmed by astrocytes? Neuron 81:961-3|
|Andrabi, Shaida A; Umanah, George K E; Chang, Calvin et al. (2014) Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A 111:10209-14|
|Krietsch, Jana; Rouleau, MichÃ¨le; Pic, Ã‰milie et al. (2013) Reprogramming cellular events by poly(ADP-ribose)-binding proteins. Mol Aspects Med 34:1066-87|
|Eacker, Stephen M; Dawson, Ted M; Dawson, Valina L (2013) The interplay of microRNA and neuronal activity in health and disease. Front Cell Neurosci 7:136|
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