Possible roles of transglutaminase-catalyzed reactions in the pathogenesis of human neurodegenerative diseases.

Abstract

Transglutaminases (TGs) are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is  the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or –OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has  been  suggested to be involved in molecular mechanisms responsible for both  physiological or pathological processes. In particular, “tissue†TG (tTG, type 2), a member of the TG  enzyme family, has been recently shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD), one of the most common food intolerances described in the western population.  In addition, numerous scientific reports show that neurodegenerative diseases, such as Alzheimer’s Disease (AD),  Parkinson’s Disease (PD), supranuclear palsy, Huntington’s Disease (HD) and  other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible roles of the transglutaminase-catalyzed reactions as molecular mechanisms responsible for such diseases, describing also some pharmacological approaches made with transglutaminase inhibitors, in order to cure diseases characterized by aberrant  transglutaminase activity.