Transglutaminases and neurodegeneration

Abstract

Eight active transglutaminases (TGs) (TGs 1-7 and factor XIIIa) are expressed in mammals, of which TGs 1-3 (Kim et al. 1999) 1 and 6 (Hadjivassilou et al. 2008) are present in human brain. The major reaction thus far attributed to the cerebral TGs is transamidation. In this reaction the carboxamide moiety of a Q residue [-C(O)NH 2 ] is converted to a substituted carboxamide [-C(O)NHR] by nucleophilic attack of an amine [RNH 2 ] such as various mono-, di-, and polyamines or the e amino group of a K residue (Lorand and Graham 2003). Of the possible transamidation linkages, theisopeptide linkage formed between Q and K resides, is the most commonly studied. GGEL bonds occur both within and between polypeptide chains, and thereby contribute to the formation of stable soluble and insoluble polymers. TGs also cross-link proteins via bis-c-glutamylpolyamine bridges between Q residues (Piacentini et al. 1988). These linkages are formed by two successive transamidations: the first utilizes a free polyamine to generate a c-glutamylpolyamine residue, which becomes the amine-bearing substrate for a second transamidation. bis-c-Glutamylpolyamine cross-links are formed at least as frequently as those involving GGEL -dependent enzymes that catalyze a variety of modifications of glutaminyl (Q) residues. In the brain, these modifications include the covalent attachment of a number of amine-bearing compounds, including lysyl (K) residues and polyamines, which serve to either regulate enzyme activity or attach the TG substrates to biological matrices. Aberrant TG activity is thought to contribute to Alzheimer disease, Parkinson disease, Huntington disease, and supranuclear palsy. Strategies designed to interfere with TG activity have some benefit in animal models of Huntington and Parkinson diseases. The following review summarizes the involvement of TGs in neurodegenerative diseases and discusses the possible use of selective inhibitors as therapeutic agents in these diseases.

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

“…It has been reported that TG activity is significantly elevated in the affected cerebral regions in Alzheimer disease, Huntington disease and supranuclear palsy (Jeitner et al, 2009). In addition, increased TG2 protein is observed in the cerebrospinal fluid of Alzheimer disease (Bonelli et al, 2002) and Parkinson disease subjects (Vermes et al, 2004).…”

“…Among them, TG 1-3 and 6 were discovered in human brain (Hadjivassiliou et al, 2008). In addition to SCA, TGs are also hypothesized to be involved in the pathogenesis of several other neurodegenerative diseases, including polyglutamine expansion diseases, Alzheimer's, Parkinson's and supranuclear palsy (Jeitner et al, 2009). However, despite extensive investigation over the last two decades, the physiologic or pathologic roles of TGs in the brain remain unclear.…”

A Profiling Platform for the Characterization of Transglutaminase 2 (TG2) Inhibitors

“…7 TG2 overactivity has been associated with inflammatory disease processes such as celiac disease, infectious diseases, cancer, and neurodegenerative diseases such as Huntington's disease (HD). [8][9][10][11] HD is an autosomal dominant, progressive neurodegenerative disease that is characterized clinically by motor, cognitive, and behavioral deficits. Specifically, TG2 expression and transglutaminase activity have been shown to be increased in the brains of HD patients and in HD mouse models.…”

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

“…Our data indicated that the modification by TG2 impaired IP 3 R1-mediated cellular processes; therefore, we hypothesized that this regulation might lead to cellular dysregulation under pathological conditions. TG2 is up-regulated in the brain in HD model mice, including R6/2 and YAC128 mice (54)(55)(56)(57), and HD patients (49,(58)(59)(60)(61). Therefore, we tested whether IP 3 R was modified by TG2 in these HD models.…”

“…S1 A-C). The Ca 2+ dependence, elution profile of the activity, and inhibition with cystamine led us to postulate that the crosslinking might be catalyzed by a TG, most likely TG2 (34,49).…”