Localization of transglutaminase in hippocampal neurons: implications for                Alzheimer's disease.

Appelt, Denah M.; Kopen, Gene C.; Boyne, Lesley J.; Balin, Brian J.

doi:10.1177/44.12.8985134

Cited by 69 publications

(41 citation statements)

References 26 publications

(34 reference statements)

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“…1 Recently, TG2 has also been shown to display other enzymatic activities, such as GTPase, 2 ATPase activities, 3 and isomerase 4 activities. TG2 expression has been reported both in the intracellular 5 and extracellular matrix. 6 Genetic deletion of TG2 in mice has demonstrated a role for TG2 activity in mitochondrial energy function.…”

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confidence: 99%

A Profiling Platform for the Characterization of Transglutaminase 2 (TG2) Inhibitors

et al. 2010

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Huntington's disease (HD) is associated with increased expression levels and activity of tissue transglutaminase (TG2), an enzyme primarily known for its cross-linking of proteins. To validate TG2 as a therapeutic target for HD in transgenic models and for eventual clinical development, a selective and brain-permeable inhibitor is required. Here, a comprehensive profiling platform of biochemical and cellular assays is presented which has been established to evaluate the potency, cellular efficacy, subtype selectivity and the mechanism-of-action of known and novel TG2 inhibitors. Several classes of inhibitors have been characterized including: the commonly used pseudo-substrate inhibitors, cystamine and putrescine (which are generally nonspecific for TG2 and therefore not practical for drug development), the various peptidic inhibitors that target the active site cysteine residue (which display excellent selectivity but in general have poor cellular activity), and the allosteric reversible small-molecule hydrazides (which show poor selectivity and a lack of cellular activity and could not be improved despite considerable medicinal chemistry efforts). In addition, a set of inhibitors identified from a collection of pharmacologically active compounds was found to be unselective for TG2. Moreover, inhibition at the guanosine triphosphate binding site has been examined, but apart from guanine nucleotides, no such inhibitors have been identified. In addition, the promising pharmacological profile of a TG2 inhibitor is presented which is currently in lead optimization to be developed as a tool compound. (Journal of Biomolecular Screening 2010:478-487)

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confidence: 99%

A Profiling Platform for the Characterization of Transglutaminase 2 (TG2) Inhibitors

et al. 2010

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“…Subsequently, tTG protein was demonstrated within amyloid plaques in AD brains (22). By using immunohistochemistry and an antibody to coagulation factor XIII, an extracellular TGase that cross-reacts with tTG, co-localization with paired helical filaments, the major components of neurofibrillary tangles (NFTs) in AD neurons were reported further suggesting a role for tTG in AD pathogenesis (23). Consistent with this notion, the phosphorylated microtubule protein, tau, a molecular component of NFTs and paired helical filaments, associates with tTG to form insoluble filaments (24).…”

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confidence: 99%

Intron-Exon Swapping of Transglutaminase mRNA and Neuronal Tau Aggregation in Alzheimer's Disease

Citron¹,

SantaCruz²,

Davies³

et al. 2001

Journal of Biological Chemistry

102

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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 TGasemediated 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.Transglutaminases (TGases, 1 EC 2.3.3.13) are a gene family of transamidating enzymes that, under the influence of calcium, catalyze protein cross-linking through acyl transfer of specific glutamine residues to lysines. These enzymes are involved in a variety of key metabolic processes that range from blood coagulation to cell death. Expression for the most ubiquitous intracellular member, tissue TGase (tTG), is highly regulated. It is induced in cultured cells by various agents including cytokines, such as interleukin-6 (IL-6) (1, 2), cyclic AMP (3-5), activation of the transcription factor, NFB (6 -8), and DNA methylation (9). The most potent inducers of tTG gene expression are retinoids (10 -12), which also promote apoptosis in various cells (13,14), including neurons (15-17).In this context, the history of tTG in Alzheimer's disease (AD) pathogenesis began almost 20 years ago with the report that brain tTG catalyzed cross-linking of neurofilament molecules (18). A decade later, A␤ peptide (19,20) as well as the ␤-amyloid precursor protein (21) were shown to be cross-linked by tTG. Subsequently, tTG protein was demonstrated within amyloid plaques in AD brains (22). By using immunohistochemistry and an antibody to coagulation factor XIII, an extracellular TGase that cross-reacts with tTG, co-localization with paired helical filaments, the major components of neurofibrillary tangles (NFTs) in AD neurons were reported further suggesting a role for tTG in AD pathogenesis (23). Consistent with this notion, the phosphor...

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“…As a member of the transglutaminase family, tissue transglutaminase catalyzes a calcium-dependent acyl transfer reaction between the ␥-carboxamide group of a peptide bound glutamine residue and either an ⑀-amino group of peptide bound lysine yielding a isopeptide bond or the primary amino group of a polyamine resulting in a (␥-glutamyl)-polyamine bond (9). Tissue transglutaminase is found within neurons (10,11) and has been implicated in a variety of processes including apoptosis (12) and axonal growth and regeneration (13,14). Because the polypeptide bound glutamine is the primary determining factor for a transglutaminase substrate, Green (7) hypothesized that there may be a threshold effect and that the addition of glutamine residues beyond a certain number may allow the mutant protein to be modified by transglutaminase and result in the formation of cross-linked products.…”

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Distinct Nuclear Localization and Activity of Tissue Transglutaminase

Lesort

Attanavanich

Zhang

et al. 1998

Journal of Biological Chemistry

157

143

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Tissue transglutaminase is a calcium-dependent transamidating enzyme that has been postulated to play a role in the pathology of expanded CAG repeat disorders with polyglutamine expansions expressed within the affected proteins. Because intranuclear inclusions have recently been shown to be a common feature of many of these codon reiteration diseases, the nuclear localization and activity of tissue transglutaminase was examined. Subcellular fractionation of human neuroblastoma SH-SY5Y cells demonstrated that 93% of tissue transglutaminase is localized to the cytosol. Of the 7% found in the nucleus, 6% copurified with the chromatinassociated proteins, and the remaining 1% was in the nuclear matrix fraction. In situ transglutaminase activity was measured in the cytosolic and nuclear compartments of control cells, as well as cells treated with the calcium-mobilizing agent maitotoxin to increase endogenous tissue transglutaminase activity. These studies revealed that tissue transglutaminase was activated in the nucleus, a finding that was further supported by cytochemical analysis. Immunofluorescence studies revealed that nuclear proteins modified by transglutaminase exhibited a discrete punctate, as well as a diffuse staining pattern. Furthermore, different proteins were modified by transglutaminase in the nucleus compared with the cytosol. The results of these experiments clearly demonstrate localization of tissue transglutaminase in the nucleus that can be activated. These findings may have important implications in the formation of the insoluble nuclear inclusions, which are characteristic of codon reiteration diseases such as Huntington's disease and the spinocerebellar ataxias.

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Localization of transglutaminase in hippocampal neurons: implications for Alzheimer's disease.

Cited by 69 publications

References 26 publications

A Profiling Platform for the Characterization of Transglutaminase 2 (TG2) Inhibitors

A Profiling Platform for the Characterization of Transglutaminase 2 (TG2) Inhibitors

Intron-Exon Swapping of Transglutaminase mRNA and Neuronal Tau Aggregation in Alzheimer's Disease

Distinct Nuclear Localization and Activity of Tissue Transglutaminase

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