Ba. Citron et al., Intron-exon swapping of transglutaminase mRNA and neuronal tau aggregationin Alzheimer's disease, J BIOL CHEM, 276(5), 2001, pp. 3295-3301
In order to understand the mechanism for insoluble neurotoxic protein polym
erization in Alzheimer's disease (AD) brain neurons, we examined protein an
d gene expression for transglutaminase (TGase 2; tissue transglutaminase (t
TG)) in hippocampus and isocortex. We found co-localization of tTG protein
and activity with tau-positive neurofibrillary tangles, whereas mRNA and se
quence analysis indicated an absolute increase in tTG; synthesized. Althoug
h apoptosis in AD hippocampus is now an established mode of neuronal cell d
eath, no definite underlying mechanism(s) is known. Since TGase-mediated pr
otein aggregation is implicated in polyglutamine ((CAG)(n)/Q(n) expansion)
disorder apoptosis, and expanded Q(n) repeats are excellent TGase substrate
s, a role for TG;ase in AD is possible. However, despite such suggestions a
lmost 20 years ago, the molecular mechanism remained elusive. We now presen
t one possible molecular mechanism for tTG-mediated, neurotoxic protein pol
ymerization leading to neuronal apoptosis in AD that involves not its subst
rates (like Q(n) repeats) but rather the unique presence of alternative tra
nscripts of tTG; mRNA In addition to a full-length (L) isoform in aged non-
demented brains, we found a short isoform (S) lacking a binding domain in a
ll AD brains. Our current results identify intron-exon "switching" between
L and S isoforms, implicating G-protein-coupled signaling pathways associat
ed with tTG that may help to determine the dual roles of this enzyme in neu
ronal life and death processes.