Transglutaminase inhibition: A therapy to protect cells from death in neurodegeneration?

Transglutaminases (TGs; E.C. 2.3.2.13) are ubiquitous enzymes which catalyze post-translational modifications of proteins. TGs and TG-catalyzed post-translational modifications of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases. In particular, TG activity has been hypothesized to also be involved also in the molecular mechanisms responsible for human neurodegenerative diseases. In support of this hypothesis, Basso et al recently demonstrated that the TG inhibition protects against oxidative stress-induced neuronal death, suggesting that multiple TG isoforms participate in oxidative stress-induced cell death and that nonselective TG isoform inhibitors will be most effective in fighting oxidative death in neurological disorders. In this commentary, we discuss the possible molecular mechanisms by which TG activity could be involved in the pathogenesis of neurological diseases, with particular reference to neurodegenerative diseases, and the possible involvement of multiple TG isoforms expressed simultaneously in the nervous system in these diseases. Moreover, therapeutic strategies based on the use of selective or nonselective TG inhibitors for the amelioration of the symptoms of patients with neurological diseases, characterized by aberrant TG activity, are also discussed.