Ablation of type 2 transglutaminase results in autophagy induction and in modulation of antioxidant defences.

Aims 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 the nervous tissue and reportedly involved in neurodegenerative disorders, possibly through its action in insoluble aggregate formation and 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 various brain regions and liver of TG2-/- mice. Methods Expression levels of superoxide dismutase 1 and 2 (SOD1, SOD2), catalase (CAT) and glutathione peroxidase 1/2 (GPx 1/2), Beclin1, LC3 and Ambra1 were evaluated by western blotting (WB) and immunohistochemistry in the neocortex, hippocampus, brainstem, and cerebellum, as well as in the liver, of 12-month-old TG2-/- and wild-type (WT) mice. Ultrastructural analyses were carried out on the same organs. Results and Conclusions WB 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 modulatory role played by TG2, related to its interaction with Beclin1. Electron microscopic analyses show some abnormal features in TG2-/- neurons, including intranuclear vacuoles. Concerning antioxidants, upregulation or downregulation of specific enzymes, strictly dependent on the brain area considered, are observed. A specific involvement of mitochondrial and peroxisomal dysfunction is suggested in TG2-/- mice.