title: Transglutaminase is a therapeutic target for oxidative stress, excitotoxicity and stroke: a new epigenetic kid on the CNS block.
abstract: Transglutaminases (TGs) are multifunctional, calcium-dependent enzymes that have been recently implicated in stroke pathophysiology. Classically, these enzymes are thought to participate in cell injury and death in chronic neurodegenerative conditions via their ability to catalyze covalent, nondegradable crosslinks between proteins or to incorporate polyamines into protein substrates. Accumulating lines of inquiry indicate that specific TG isoforms can shuttle into the nucleus when they sense pathologic changes in calcium or oxidative stress, bind to chromatin and thereby transduce these changes into transcriptional repression of genes involved in metabolic or oxidant adaptation. Here, we review the evidence that supports principally a role for one isoform of this family, TG2, in cell injury and death associated with hemorrhagic or ischemic stroke. We also outline an evolving model in which TG2 is a critical mediator between pathologic signaling and epigenetic modifications that lead to gene repression. Accordingly, the salutary effects of TG inhibitors in stroke may derive from their ability to restore homeostasis by removing inappropriate deactivation of adaptive genetic programs by oxidative stress or extrasynaptic glutamate receptor signaling.
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605, USA. mab2080@med.cornell.edu
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011503:Transglutaminases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D011503:Transglutaminases