Intron-exon swapping of transglutaminase mRNA and neuronal Tau aggregation in Alzheimer's disease.
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)/Q(n) expansion) disorder apoptosis, and expanded Q(n) 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 Q(n) 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.
Citron
B A
BA
Neurobiology Research Lab, Heartland Veterans Integrated Service Network, Kansas City, Missouri 64128, USA.
SantaCruz
K S
KS
Davies
P J
PJ
Festoff
B W
BW
D017398:Alternative Splicing / Q000235:genetics; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D018076:DNA, Complementary / Q000032:analysis; D005091:Exons; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013997:Time Factors; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D018076:DNA, Complementary; D012333:RNA, Messenger; D016875:tau Proteins; D011503:Transglutaminases