Neurodegenerative diseases and transglutaminase

The idea that transglutaminase (TG), a posttranslational protein crosslinking enzyme (for reviews, see refs. 1–6), might be involved in the pathology of neurodegenerative diseases, notably of Alzheimer disease (AD), was first suggested by the experiments of Selkoe et al. (7, 8). These authors drew particular attention to the reactions of TG with brain neurofilaments. Miller and Anderton (9) extended the observations by showing that, in addition to the neurofilament triplet proteins, the microtubule-associated proteins were also good substrates for TG. The dynamic quality of the neural intermediate filament network (10) is essential for maintaining the plasticity of the cytoskeleton and cell architecture, in general. Linking together noncovalently assembled segments of the network with intermolecular Nɛ(γ-glutamyl)lysine side chain bridges could impact adversely on the functions and viability of the neuron. Efforts are underway for documenting the TG-mediated covalent polymerization of the microtubule-associated τ proteins (11, 12) which are the main (if not the only) constituents of the intracellular neurofibrillary tangles (or paired helical filaments; PHF) often seen in AD (13) and other diseases (14). With recombinant human τ40 protein as substrate for human TG, a number of potential crosslinking sites were identified by employing dansylcadaverine for the enzyme-directed substitutions of Gln (or acceptor) residues (15) and dansyl-ɛ-aminocaproyl Gln-Gln-Ile-Val for those of the Lys (or donor) residues (16). Listed roughly in the order of reactivities, the following side chains in τ40 were derivatized: Gln-424, -88, -6, -244, -351, -124, -276, and -288; Lys-383, -385, -174, -180, -225, -263, and -24 (S. N. P. Murthy, J. A. Kuret, J. Wilson, T. J. Lukas, and L.L., unpublished). It remains to be determined which of these residues is involved in the homologous polymerization of τ to τ and which is involved in the crosslinking of τ to other neuronal …