Transglutaminase Inhibition as a Possible Therapeutical Approach to Protect Cells from Death in Neurodegenerative Diseases

Abstract

Transglutaminases 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. Recently, "tissue" transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to celiac disease. 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 therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates to cysteamine and derivatives.

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

“…new avenues for neurodegenerative therapeutic research (43). It is interesting to note that we found that AMI significantly attenuated the expression of transglutaminase 2 in the hippocampus and the striatum.…”

“…For example, Tppp (tubulin polymerization-promoting protein) and Acsl5 (acyl-CoA synthetaselong-chainfamilymember5)andSdhc(succinatedehydrogenase complex, subunit C, integral membrane protein, 15 kDa) are strongly implicated in mitochondrial function and metabolic support (81)(82)(83). AMI also consistently up-regulated the expression of factors associated with neuronal development (Sparc, secreted protein, acidic, cysteine-rich (osteonectin)) (84), neuronal Akt-mediated protection (Nyap1, neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adaptor 1), and attenuation of neurodegenerative cross-linking (Tgm2, transglutaminase 2) (43,85). With our use of PAGE MSigDB bioinformatics analysis (Fig.…”

Current and Emerging Topical Antibacterials and Antiseptics: Agents, Action, and Resistance Patterns

“…Numerous systemic and topical antibiotic and antiseptic agents have been used for the prevention and treatment of burn wound infections (BWI), with the rationale for application of topical therapy predominantly related to prophylaxis of BWI. It is postulated that topical therapy may reduce the microbial burden in the burn wound, thereby reducing the risk of infection and potentially promoting wound healing (36,37,40,41).…”

New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds

“…Several clinical trials are being tested for TGase 2 inhibitors. Cysteamine is known to target active site cysteine residues and has been launched as a potential therapeutic for a broad range of disease indications including cystic fibrosis [20], neurodegenerative diseases [21], and Huntington’s disease [22], amongst others by Raptor pharmaceuticals, Mylan, and the European Institute for Cystic Fibrosis Research [19]. Zedira has focused on developing peptidomimetic TGase 2 inhibitors which mimick the TGase 2 substrate for the treatment of celiac disease.…”