Intron-exon swapping of transglutaminase mRNA and neuronal tau aggregationin Alzheimer's disease

Citation
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
Citations number
96
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
5
Year of publication
2001
Pages
3295 - 3301
Database
ISI
SICI code
0021-9258(20010202)276:5<3295:ISOTMA>2.0.ZU;2-3
Abstract
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.