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Papers In Press, published online ahead of print September 29, 2000
J. Biol. Chem, 10.1074/jbc.M004776200
Submitted on June 1, 2000
Revised on September 14, 2000
Accepted on September 29, 2000
Neurobiology Research Lab 151, Heartland Veterans Health Service Network, Kansas City, MO 64128-2295
Corresponding Author: serpin{at}eagle.cc.ukans.edu
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; tTG) in hippocampus and isocortex. We found co-localization of tTG protein and activity with tau-positive neurofibrillary tangles (NFTs), while 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 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.
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