Complete transglutaminase 2 ablation results in reduced stroke volumes and astrocytes that exhibit increased survival in response to ischemia

Abstract

Transglutaminase 2 (TG2) is a very multifunctional protein that is ubiquitously expressed in the body. It is a Ca2+-dependent transamidating enzyme, a GTPase, as well as a scaffolding protein. TG2 is the predominant form of transglutaminase expressed in the mammalian nervous system. Previously, it was shown that TG2 can affect both cell death and cell survival mechanisms depending on the cell type and the stressor. In the case of ischemic stress, TG2 was previously shown to play a protective role in the models used. For example in hTG2 transgenic mice, where TG2 is overexpressed only in neurons, middle cerebral artery ligation (MCAL) resulted in smaller infarct volumes compared to wild type mice. In this study TG2 knock out mice were used to determine how endogenous TG2 affected stroke volumes. Intriguingly, infarct volumes in TG2 knock out mice were significantly smaller compared to wild type mice. As expected, primary neurons isolated from TG2 knock out mice showed decreased viability in response to oxygen-glucose deprivation. However, primary astrocytes that were isolated from TG2 knock out mice were resistant to oxygen-glucose deprivation in situ. Both wild type and knock out neurons were protected against oxygen glucose deprivation when they were co-cultured with astrocytes from TG2 knockout mice. Therefore, the decreased stroke volumes observed in TG2 knock out mice after MCAL, can be correlated with the protective effects of TG2 knock out in astrocytes in response to oxygen glucose deprivation in situ. These findings suggest that neuron-astrocyte crosstalk plays a significant role in mediating ischemic cell death and that TG2 differentially impacts cell survival depending on cell context.

Pituitary Adenylate Cyclase-activating Polypeptide Type 1 Receptor (PAC1) Gene Is Suppressed by Transglutaminase 2 Activation

“…The present finding that CHOP, GRP78, and cleaved caspase-3 were attenuated by the pretreatment with cystamine supports the previous report that the downstream activity of TG2 activates the calpain/caspase pathway (32). Also, knocking down of TG2 expression significantly attenuated their cell death (data not shown), In fact, it was reported previously that infarct volumes in TG2-knockout mice were significantly smaller compared with those in wild type mice (33), suggesting that TG2 is a potential target for development of therapeutics of brain ischemia.…”

Transglutaminase is a Therapeutic Target for Oxidative Stress, Excitotoxicity and Stroke: A new Epigenetic Kid on the Cns Block

“…45 Interestingly, TG1 and 2 can be upregulated by different groups of cytokines (e.g., TNFa, IL-6, and TGFb) or toxins (lipopolysachharide) in mixed astrocyte-neuronal cultures. 46 By contrast to our in vitro data that shows that both TG1 and TG2 are required for cell death from oxidative death, TG2 ablation reduced the infarct volume in a model of permanent ischemia 47 and its overexpression in neurons via a Prp promoter, showed higher number of apoptotic cells and greater susceptibility to kainate stimuli. 48 Future studies will clarify why TG2 is necessary and sufficient in some paradigms, while TG2 and TG1 are necessary in other paradigms.…”

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

“…Neurons from TG2 knockout mice showed decreased viability in response to oxygen-glucose deprivation, which was not observed in astrocytes, as they were resistant to oxygen-glucose deprivation in situ. Interestingly, wild type and knock out neurons were protected against oxygen glucose deprivation when they were co-cultured with astrocytes from TG2 knockout mice (Colak G 2012). Therefore, the decreased stroke volumes observed in TG2 knock out evidences that its expression is more important in astrocytes.…”