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

被引:89
作者
Citron, BA
SantaCruz, KS
Davies, PJA
Festoff, BW
机构
[1] Heartland Vet Integrated Serv Network, Neurobiol Res Lab, Kansas City, MO 64128 USA
[2] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66160 USA
[3] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA
[4] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA
[5] Univ Texas, Hlth Sci Ctr, Dept Integrated Biol Pharmacol & Physiol, Houston, TX 77225 USA
关键词
D O I
10.1074/jbc.M004776200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 TG;ase 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.
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页码:3295 / 3301
页数:7
相关论文
共 96 条
[21]   RETINOIDS AS GENERALIZED REGULATORS OF CELLULAR GROWTH AND DIFFERENTIATION [J].
DAVIES, PJA ;
BASILION, JP ;
CHIOCCA, EA ;
JOHNSON, J ;
PODDAR, S ;
STEIN, JP .
AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 1988, 296 (03) :164-170
[22]   A COMPREHENSIVE SET OF SEQUENCE-ANALYSIS PROGRAMS FOR THE VAX [J].
DEVEREUX, J ;
HAEBERLI, P ;
SMITHIES, O .
NUCLEIC ACIDS RESEARCH, 1984, 12 (01) :387-395
[23]   Identification of tissue transglutaminase as the autoantigen of celiac disease [J].
Dieterich, W ;
Ehnis, T ;
Bauer, M ;
Donner, P ;
Volta, U ;
Riecken, EO ;
Schuppan, D .
NATURE MEDICINE, 1997, 3 (07) :797-801
[24]  
ELALAOUI S, 1991, INT J CANCER, V48, P221
[25]   α1B-adrenoceptor interacts with multiple sites of transglutaminase II:: Characteristics of the interaction in binding and activation [J].
Feng, JF ;
Gray, CD ;
Im, MJ .
BIOCHEMISTRY, 1999, 38 (07) :2224-2232
[26]   Evidence that phospholipase delta 1 is the effector in the G(h) (transglutaminase II)-mediated signaling [J].
Feng, JF ;
Rhee, SG ;
Im, MJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (28) :16451-16454
[27]   Retinoic acid receptor γ1 (RARγ1) levels control RARβ2 expression in SK-N-BE2(c) neuroblastoma cells and regulate a differentiation-apoptosis switch [J].
Ferrari, N ;
Pfahl, M ;
Levi, G .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (11) :6482-6492
[28]   Transglutaminase induction by various cell death and apoptosis pathways [J].
Fesus, L ;
Madi, A ;
Balajthy, Z ;
Nemes, Z ;
Szondy, Z .
EXPERIENTIA, 1996, 52 (10-11) :942-949
[29]  
FRAIJ BM, 1992, J BIOL CHEM, V267, P22616
[30]   GTP hydrolysis by human tissue transglutaminase homologue [J].
Fraij, BM .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 218 (01) :45-49