Abstract
The transglutaminase (TGase) family of enzymes, of which seven different members are known in the human genome, participate in many biological processes involving cross-linking proteins into large macromolecular assemblies. The TGase 2 enzyme is known to be present in neuronal tissues and may play a role in neuronal degenerative diseases such as Alzheimer's disease (AD) by aberrantly cross-linking proteins. In this paper, we demonstrate by reverse transcriptase-polymerase chain reaction and immunological methods with specific antibodies that in fact three members, the TGase 1, TGase 2, and TGase 3 enzymes, and are differentially expressed in various regions of normal human brain tissues. Interestingly, the TGase 1 and 3 enzymes and their proteolytically processed forms are involved in terminal differentiation programs of epithelial cell development and barrier function. In addition, we found that the levels of expression and activity of the TGase 1 and 2 enzymes were both increased in the cortex and cerebellum of AD patients. Furthermore, whereas normal brain tissues contain approximately 1 residue of cross-link/10,000 residues, AD patient cortex and cerebellum tissues contain 30-50 residues of cross-link/10,000 residues. Together, these findings suggest that multiple TGase enzymes are involved in normal neuronal structure and function, but their elevated expression and cross-linking activity may also contribute to neuronal degenerative disease.
Highlights
The transglutaminase (TGase) family of enzymes, of which seven different members are known in the human genome, participate in many biological processes involving cross-linking proteins into large macromolecular assemblies
Most of the TGase 1 in epithelial cells exists as a Ϸ100-kDa membrane-bound protein of very low specific activity, but during terminal differentiation, some may be activated by proteolytic processing into a 67/33/10-kDa form of very high specific activity, and some intact low specific activity or higher specific activity processed forms are released into the cytosol [37, 42]
Unlike epithelial tissues where most TGase 1 is membrane bound, we found in these brain tissues that only about 20% of the total TGase activity was associated with membranes from the cortex and cerebellum (Fig. 4), all of which was due to the TGase 1 protein (Fig. 5)
Summary
The transglutaminase (TGase) family of enzymes, of which seven different members are known in the human genome, participate in many biological processes involving cross-linking proteins into large macromolecular assemblies. Whereas normal brain tissues contain Ϸ1 residue of cross-link/10,000 residues, AD patient cortex and cerebellum tissues contain 30 –50 residues of cross-link/10,000 residues Together, these findings suggest that multiple TGase enzymes are involved in normal neuronal structure and function, but their elevated expression and cross-linking activity may contribute to neuronal degenerative disease. In the adult human central nervous system, only the TGase 2 enzyme has been identified by immunohistochemical studies [19] In neurons of both the peripheral and central nervous systems, several different bands of TGase were observed [21]. TGase activities with different biochemical characteristics were reported in sympathetic postganglionic motorneurons of the rat peripheral nervous system [23] and in the adult human central nervous system [24] the nature of the TGase(s) was not identified. We extend an earlier report [29] to show that the levels of both TGases 1 and 2 are changed and increased in various parts of the brain in AD disease concomitant with significant levels of isopeptide cross-link formed by these enzymes
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