Type 2 or “tissue” transglutaminase (TG2) is a ubiquitous calcium-dependent acyl-transferase, regulating cell processes, including apoptosis and autophagy. TG2 is highly expressed in hepatic and nervous tissues, and is reportedly involved in neurodegenerative disorders, possibly in the response to oxidative stress. The present study aims to clarify the role of TG2 in redox balance and autophagy. To this purpose, the expression levels of antioxidant enzymes and pro-autophagic proteins were investigated in the liver and brain of TG2-/- mice. Expression of superoxide dismutase 1 and 2 (SOD1, SOD2), catalase (CAT) and glutathione peroxidase 1/2 (GPx1/2), Beclin1, LC3 and Ambra1 were evaluated by molecular and morphological approaches in the liver and in various brain regions (neocortex, hippocampus and cerebellum) of 12-month-old TG2-/- and wild-type (WT) mice. Western blotting and immunohistochemical data reveal overall higher levels of autophagic proteins (Beclin1, Ambra1 and LC3) in the brain areas considered and in the liver of TG2-/- mice, compared to their WT counterparts. This strongly argues for an induction of autophagy in the absence of a modulating role played by TG2, related to its interaction with Beclin1. Electron microscopic analyses show abnormal features in TG2-/- neurons, including intranuclear membranous vacuoles, suggesting lipid dysmetabolism. In the knockout liver, dramatic reduction of CAT and SOD2 expression is found, while GPx1/2 and SOD1 are intriguingly upregulated. In the brain, upregulation or downregulation of specific enzymes appear strictly dependent on the region considered. Since CAT is a peroxisomal enzyme and SOD2 is a mitochondrial protein, we suggest that these organelles are selectively affected in TG2-/- mice. The hypothesized mitochondrial/peroxisomal dysfunction could also explain lipid accumulation underlying myelin-like degeneration observed at the ultrastructural level. On the other hand, upregulation of GPx1/2 and SOD1, which are cytosolic enzymes, could represent a response to oxidative stress generated by failure of the mitochondrial/peroxisomal compartments.
D'Orio, B., Nardacci, R., Fanelli, F., Sepe, S., Piacentini, M., Moreno, S. (2014). Autophagy induction, modulation of antioxidant defences and abnormal ultrastructural features in transglutaminase 2 knockout mice. In GEI.