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.

Serum levels of SOD and risk of autism spectrum disorder: A case‐control study

“…A number of studies have implicated oxidative stress as a major upstream component in the signaling cascade involved in activation of redox‐sensitive transcription factors and pro‐inflammatory gene expression leading to inflammatory response (Rossignol and Frye, 2012a). Fourth, excitotoxicity has been suggested as a result of oxidative stress (Basso and Ratan, 2013). Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients (Essa et al, 2013).…”

Essential Role of Transglutaminase 2 in Vascular Endothelial Growth Factor–Induced Vascular Leakage in the Retina of Diabetic Mice

“…Several low-molecular-weight inhibitors have been reported to prevent TGase2 transamidating activity, and the most widely used TGase inhibitor in vivo is cystamine (23). Cystamine is used for the treatment of corneal crystals in nephropathic cystinosis (34,35).…”

“…TGase2 is expressed ubiquitously and is implicated in various cellular processes including cell death, proliferation, adhesion, migration, and cytoskeletal reorganization (13)(14)(15). TGase2 is also associated with various diseases, including cardiovascular diseases (16), inflammation (17,18), celiac disease (19,20), neurodegenerative disorders (21,22), and hemorrhagic or ischemic stroke (23). TGase2 is expressed in ocular tissues, including the retina and lens, and is possibly associated with ocular diseases including cataract and glaucoma (18,24,25).…”

Cysteamine prevents vascular leakage through inhibiting transglutaminase in diabetic retina

“…In this study, intravitreal injection of cysteamine prevented hyperglycemia-induced TGase activation and vascular leakage in the retinas of diabetic mice. Low-molecular-weight inhibitors prevent TGase transamidating activity, and the most widely used TGase inhibitor is cystamine, the dimer form of cysteamine (Basso & Ratan 2013). Previous clinical and preclinical trials using cystamine for treatment of neurodegenerative diseases and cystic fibrosis suggest that cystamine could be used for prevention of diabetic vascular leakage.…”