Transglutaminase Activity, Protein, and mRNA Expression Are Increased in Progressive Supranuclear Palsy

Abstract

Transglutaminases catalyze the covalent cross-linking of substrate proteins to form insoluble protein complexes that are resistant to degradation. Our previous studies demonstrated that transglutaminase-induced cross-linking of tau proteins occurs in Alzheimer disease and progressive supranuclear palsy (PSP). The current study was designed to measure transglutaminase enzyme activity and the mRNA and protein levels of 3 transglutaminase isoforms that are expressed in human brain. Overall, transglutaminase activity was significantly increased in the globus pallidus (182% of control) and pons in PSP (171% of control) but not the occipital cortex (a region spared from pathology). Using a Spearman rank correlation test, we found that tissues with more transglutaminase-activity had more neurofibrillary tangles. Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.

Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice

“…Transglutaminase enzymatic activity was determined in the spinal cord of P301L tau, 4RWT tau, and nontransgenic mice by measuring the incorporation of a radioactive polyamine donor ( 3 H-putrescine) into an exogenous protein acceptor (casein). Our laboratory has previously published the detailed procedure used for this assay (Zemaitaitis et al, 2003). Transglutaminase activity was measured for each animal in two separate assays, and, within an assay, each sample was measured in triplicate.…”

“…Aberrant elevations in transglutaminase activity have been demonstrated in brain regions with neurofibrillary pathology in two human tauopathies (Johnson et al, 1997;Zemaitaitis et al, 2003). Because the spinal cord of P301L tau transgenic mice has been shown previously to develop abundant NFT , we measured the transglutaminase activity in the spinal cord of P301L tau, 4RWT tau, and nontransgenic mice.…”

“…Specifically, two glutamine and 10 lysine residues in tau are modified by transglutaminase in vitro (Murthy et al, 1998). Transglutaminase activity (Johnson et al, 1997;Zemaitaitis et al, 2003) and transglutaminase-catalyzed bonds in PHFs and NFTs (Balin et al, 1999;Norlund et al, 1999;Zemaitaitis et al, 2000;Singer et al, 2002) are significantly elevated in brain regions with abundant neurofibrillary pathology in both AD and PSP. Furthermore, transglutaminase-catalyzed bonds are present in PHF tau before NFTs are microscopically detectable, implicating transglutaminase cross-linking of tau protein as an early event in NFT formation (Singer et al, 2002).…”

Mitochondrial Aconitase is a Transglutaminase 2 Substrate: Transglutamination is a Probable Mechanism Contributing to High-Molecular-Weight Aggregates of Aconitase and Loss of Aconitase Activity in Huntington Disease Brain

“…For example, inherent TGase activity is increased in affected brain regions in several neurodegenerative diseases, including Huntington disease (HD) (2)(3)(4), Alzheimer disease (AD) (5-7), Parkinson disease (PD) (8) and supranuclear palsy (9). GGEL linkages have been detected in protein aggregates in AD-and HD brain (6,10,11), and free GGEL isodipeptide is increased in HD brain (10), HD CSF (12) and AD CSF (13).…”

Possible Role of the Transglutaminase Activity in Molecular Mechanisms Responsible for Human Neurodegenerative Diseases

“…By these molecular mechanisms, TGs could contribute to AD symptoms and progression [38] . Moreover, there is evidence that TGs also contribute to the formation of proteinaceous deposits in Parkinson's Disease (PD) [39,40] , in supranuclear palsy [41,42] and in HD, a neurodegenerative disease caused by a CAG expansion in the affected gene [43] . For example, expanded polyglutamine domains have been reported to be substrates of TG2 [44][45][46] and therefore aberrant TG activity could contribute to CAG-expansion diseases, including HD ( Figure 3).…”