Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases.

Abstract

Transglutaminases  are a family of  Ca²⁺-dependent 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, transglutaminase activity has been shown to be responsible for a widespread human autoimmune disease, the Celiac Disease.  Interestingly, neurodegenerative diseases, such as Alzheimer’s Disease,  Parkinson’s Disease, supranuclear palsy, Huntington’s Disease 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 molecular mechanisms responsible for such diseases and on the possible therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant  transglutaminase activity.