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 thesymptoms of patients with neurological diseases,characterized by aberrant TG activity,are also discussed.

Physio-pathological roles of transglutaminase-catalyzed reactions

Transglutaminases(TGs) are a large family of related and ubiquitous enzymes that catalyze post-translational modifications of proteins.The main activity of these enzymes is the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue 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 the absence of co-substrates,the nucleophile may be water,resulting in the net deamidation of the glutaminyl residue.The TG enzymes are also capable of catalyzing other reactions important for cell viability.The distribution and the physiological roles of TG enzymes have been widely studied in numerous cell types and tissues and their roles in several diseases have begun to be identified."Tissue" TG(TG2) ,a member of the TG family of enzymes,has definitely been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology:i.e.celiac disease(CD) .TG activity has alsobeen hypothesized to be directly involved in the pathogenetic mechanisms responsible for several other human diseases,including neurodegenerative diseases,which are often associated with CD.Neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease,supranuclear palsy,Huntington's disease and other recently identified polyglutamine diseases,are characterized,in part,by aberrant cerebral TG activity and by increased cross-linked proteins in affected brains.In this review,we discuss the physio-pathological role of TG-catalyzed reactions,with particular interest in the molecular mechanisms that could involve these enzymes in the physio-pathological processes responsible for human neurodegenerative diseases.