Possible physiopathological effects of the transglutaminase activity on the molecular mechanisms responsible for human neurodegenerative diseases.
Transglutaminases are a class of 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. Recently, 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.
Martina
M
Iannaccone
Federica
F
Titta
Enrica
E
Serretiello
Marco
M
Monfregola
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy. vittorio.gentile@unina2.it.
Vittorio
V
Gentile
D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*
D018696:Neuroprotective Agents; D011503:Transglutaminases