Transglutaminases (TGs) are ubiquitous calcium-dependent acyl-transferases, catalysing post-translational protein modifications. Among the family members, TG2 (or "tissue" transglutaminase) acts as a multifunctional protein regulating cell processes, including autophagy [1,2]. TG2 is highly expressed in the nervous tissue and reportedly involved in neurodegenerative disorders . Indeed, the pathophysiology of these diseases includes insoluble aggregate formation, and covalent cross-linking of pathogenic proteins by TG2 has been suggested. Another hallmark of neurodegeneration is dysregulated autophagy, thus making the role played by TG2 in this cellular process especially relevant. The present study aims to clarify the role of TG2 in neuronal ultrastructure as well as redox balance and autophagy. Electron microscopic analyses were carried out in various brain regions, namely neocortex, hippocampus, brainstem, and cerebellum of 12-month-old TG2-/- and wild-type (WT) mice. TG2-/- neurons show abnormal features including intranuclear vacuoles surrounded by a single membrane and aberrant autophagic bodies. Moreover, the expression levels of antioxidant enzymes and pro-autophagic proteins were investigated in the same brain regions. Superoxide dismutase 1 and 2 (SOD1, SOD2), catalase (CAT), glutathione peroxidase 1/2 (GPx 1/2), Beclin1, LC3 and Ambra1 were evaluated by western blotting (WB) and immunohistochemistry. Overall higher levels of autophagic proteins in the brain areas considered, compared to their WT counterparts, were detected. This strongly argues for an induction of autophagy in the absence of a modulatory role played by TG2, related to its interaction with Beclin1. Concerning antioxidants, upregulation or downregulation of specific enzymes, strictly dependent on the brain area considered, were observed. A specific involvement of mitochondrial and peroxisomal dysfunction is suggested in TG2-/- mice.
D'Orio, B., Nardacci, R., Fanelli, F., Sepe, S., Piacentini, M., Moreno, S. (2014). Intranuclear vacuoles in neurons of a mouse model lacking type 2 transglutaminase. In Biophysics.