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Originally published In Press as doi:10.1074/jbc.M004776200 on September 29, 2000

J. Biol. Chem., Vol. 276, Issue 5, 3295-3301, February 2, 2001
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Intron-Exon Swapping of Transglutaminase mRNA and Neuronal Tau Aggregation in Alzheimer's Disease*

Bruce A. CitronDagger §, Karen S. SantaCruz, Peter J. A. Davies||, and Barry W. FestoffDagger §**Dagger Dagger

From the Dagger  Neurobiology Research Lab, Heartland Veterans Integrated Service Network, Kansas City, Missouri 64128, the § Departments of Neurology,  Pathology and Laboratory Medicine, and ** Pharmacology, Toxicology, and Therapeutics, the University of Kansas Medical Center, Kansas City, Kansas 66160, and || Department of Integrative Biology, Pharmacology, and Physiology, University of Texas, Houston Health Science Center, Houston, Texas 77225

In order to understand the mechanism for insoluble neurotoxic protein polymerization in Alzheimer's disease (AD) brain neurons, we examined protein and gene expression for transglutaminase (TGase 2; tissue transglutaminase (tTG)) in hippocampus and isocortex. We found co-localization of tTG protein and activity with tau-positive neurofibrillary tangles, whereas mRNA and sequence analysis indicated an absolute increase in tTG synthesized. Although apoptosis in AD hippocampus is now an established mode of neuronal cell death, no definite underlying mechanism(s) is known. Since TGase-mediated protein aggregation is implicated in polyglutamine ((CAG)n/Qn expansion) disorder apoptosis, and expanded Qn repeats are excellent TGase substrates, a role for TGase in AD is possible. However, despite such suggestions almost 20 years ago, the molecular mechanism remained elusive. We now present one possible molecular mechanism for tTG-mediated, neurotoxic protein polymerization leading to neuronal apoptosis in AD that involves not its substrates (like Qn repeats) but rather the unique presence of alternative transcripts 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 all AD brains. Our current results identify intron-exon "switching" between L and S isoforms, implicating G-protein-coupled signaling pathways associated with tTG that may help to determine the dual roles of this enzyme in neuronal life and death processes.

* This work was supported by the Department of Veterans Affairs Medical Research Service (to B. W. F.), Missouri Alzheimer's and Related Disorders Fund (to B. W. F.), the University of Kansas Medical Center Research Institute, Inc. (to B. W. F. and K. S. C.), and the Midwest Biomedical Research Foundation (to B. A. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: Neurobiology Research Lab (151), Heartland Veterans Health Service Network, Veterans Affairs Medical Center, 4801 Linwood Blvd., Kansas City, MO 64128. Tel.: 816-861-4700 (ext. 7079); Fax: 816-922-3375; E-mail: serpin@eagle.cc.ukans.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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