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The protein transglutaminase 2 (TG2) has been implicated as a modulator of neuronal viability. TG2's role in mediating cell survival processes has been suggested to involve its ability to alter transcriptional events. The goal of this study was to examine the role of TG2 in neuronal survival and to begin to delineate the pathways it regulates. We show that depletion of TG2 significantly compromises the viability of neurons in the absence of any stressors. RNA sequencing revealed that depletion of TG2 dysregulated the expression of 86 genes with 59 of these being upregulated. The genes that were upregulated by TG2 knockdown were primarily involved in extracellular matrix function, cell signaling and cytoskeleton integrity pathways. Finally, depletion of TG2 significantly reduced neurite length. These findings suggest for the first time that TG2 plays a crucial role in mediating neuronal survival through its regulation of genes involved in neurite length and maintenance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The increased activity of transglutaminase 2 (TG2) in various inflammatory and fibrotic conditions results in the development of numerous disease processes. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is an inflammatory and demyelinating disease of the central nervous system and is mediated by many inflammatory cytokines and mediators. We examined the role of TG2 in encephalitogenic CD4(+) T cell responses and EAE development using mice lacking TG2 (TG2(-/-)). TG2(-/-) mice showed decreased disease severity as compared with wild-type (WT) mice. Treatment with cysteamine, a TG2 inhibitor, ameliorated disease severity in WT mice. Exacerbated disability in WT mice resulted from the increased infiltration of cytokine-producing CD4(+) T cells and sustained expression of inflammatory cytokines and mediators in the lesion. The increased number of IL-17- and IFN-γ-producing cells in the spinal cord resulted from peripheral expansion of these cells after immunization with myelin-derived antigen. In vitro differentiation of WT and TG2(-/-) splenocytes revealed that proliferation and activation-induced cell death did not differ, but differentiation into IL-17- or IFN-γ-producing cells was increased in WT mice. Adoptive transfer experiments revealed that pathogenic CD4(+) T cell differentiation and disease progression were caused by both the T cell-intrinsic and -extrinsic effects of TG2. This study is the first to report a pathogenic role for TG2 in the EAE progress and suggests that therapeutic targeting of TG2 may be effective against multiple sclerosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Transglutaminase 2 (TG2) is a very multifunctional protein that is ubiquitously expressed in the body. It is a Ca(2+)-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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Tissue transglutaminase (tTG) is a multifunctional enzyme that catalyzes peptide cross-linking and polyamination reactions, and also is a signal-transducing GTPase. tTG protein content and enzymatic activity are upregulated in the brain in Huntington's disease and in other neurological diseases and conditions. Since mouse models are currently being used to study the role of tTG in Huntington's disease and other neurodegenerative diseases, it is critical that the level of its expression in the mouse forebrain be determined. In contrast to human forebrain where tTG is abundant, tTG can only be detected in mouse forebrain by immunoblotting a GTP-binding-enriched protein fraction. tTG mRNA content and transamidating activity are approximately 70% lower in mouse than in human forebrain. However, tTG contributes to the majority of transglutaminase activity within mouse forebrain. Thus, although tTG is expressed at lower levels in mouse compared with human forebrain, it likely plays important roles in neuronal function.