Plasticity and stabilization of neuromuscular and CNS synapses: interactions between thrombin protease signaling pathways and tissue transglutaminase.
The first association of the synapse as a potential site of neurodegenerative disease burden was suggested for Alzheimer's disease (AD) almost 30 years ago. Since then protease:protease inhibitor (P:PI) systems were first linked to functional regulation of synaptogenesis and synapse withdrawal at the neuromuscular junction (NMJ) more than 20 years ago. Confirmatory evidence for the involvement of the synapse, the rate-limiting or key unit in neural function, in AD did not become clear until the beginning of the 1990s. However, over the past 15 years evidence for participation of thrombin, related serine proteases and neural PIs, homologous and even identical to those of the plasma clot cascade, has been mounting. Throughout development a balance between stabilization forces, on the one hand, and breakdown influences, on the other, becomes established at synaptic junctions, just as it does in plasma clot proteins. The formation of protease-resistant cross-links by the transglutaminase (TGase) family of enzymes may add to the stability for this balance. The TGase family includes coagulation factor XIIIA and 8 other different genes, some of which may also influence the persistence of neural connections. Synaptic location of protease-activated, G-protein-coupled receptors (PARs) for thrombin and related proteases, their serpin and Kunitz-type PIs such as protease nexin I (PNI), alpha1-antichymotrypsin (alpha-ACT), and the Kunitz protease inhibitor (KPI)-containing secreted forms of beta-amyloid protein precursor (beta-APP), along with the TGases and their putative substrates, have all been amply documented. These findings strongly add to the conclusion that these molecules participate in the eventual structural stability of synaptic connections, as they do in coagulation cascades, and focus trophic activity on surviving terminals during periods of selective contact elimination. In disease states, this imbalance is likely to be shifted in favor of destabilizing forces: increased and/or altered protease activity, enhanced PAR influence, decreased and/or altered protease inhibitor function, reduction and/or alteration in tTG expression and activity, and alteration in its substrate profile. This imbalance further initiates a cascade of events leading to inappropriate programmed cell death and may well be considered evidence of synaptic apoptosis.
Festoff
B W
BW
Neurobiology Research Laboratory, University of Kansas Medical Center, Kansas City Veterans Affairs Medical Center, Missouri 64128, USA.
Suo
Z
Z
Citron
B A
BA
D000595:Amino Acid Sequence; D000818:Animals; D022081:Cell Surface Extensions / Q000378:metabolism; D005176:Factor XIII / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009469:Neuromuscular Junction / Q000166:cytology / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism*
D005176:Factor XIII; D011503:Transglutaminases; D012697:Serine Endopeptidases; D013917:Thrombin