Blockade of enzyme activity inhibits tissue transglutaminase-mediated transamidation of α-synuclein in a cellular model of Parkinson's disease

Verhaar, Robin; Jongenelen, Cornelis A.M.; Gérard, Melanie; Baekelandt, Veerle; Dam, Anne‐Marie van; Wilhelmus, Micha M.M.; Drukarch, Benjamin

doi:10.1016/j.neuint.2011.03.004

Cited by 34 publications

(31 citation statements)

References 60 publications

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“…For cellular TGM2 activity measurements, incorporation of 5-(biotinamido) pentylamine (BAP; Sigma, St. Louis, Mo., USA) into proteins was determined in normal or CKD RVSMC using published methods [11]. After cell culture, VSMC were washed with phosphate-buffered saline (PBS) and then incubated with culture media containing 1 m M BAP for 4 h. The cell lysate was isolated using 1% NP-40 buffer (50 m M TrisHCl, pH 7.4; 5 m M DTT; 50 m M KCL; 3 m M EDTA; 5 m M MgCl 2 ; 150 m M NaCl) and the protein concentration of the lysates was determined with the BCA assay.…”

Section: Methodsmentioning

confidence: 99%

Transglutaminase 2 Accelerates Vascular Calcification in Chronic Kidney Disease

et al. 2013

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Background: Transglutaminase 2 (TGM2) is a calcium-dependent enzyme that can cross-link nearly all extracellular matrix (ECM) proteins and can facilitate cell-ECM interaction through integrins. Given the importance of the ECM in vascular calcification we tested the hypothesis that increased TGM2 activity may accelerate vascular calcification in chronic kidney disease (CKD). Methods: We utilized thoracic aortas and vascular smooth muscle cells (VSMC) from the Cy/+ rat, a model of progressive CKD that develops arterial calcification on a normal phosphorus diet, compared to normal rats. Results: VSMC isolated from CKD rats had increased expression and activity of TGM2 compared to cells from normal rats. The increased calcification and expression of alkaline phosphatase activity observed in VSMC from CKD rats compared to normal was inhibited in a dose-dependent manner with the TGM inhibitors cystamine and Z006. Matrix vesicles (MV) from CKD rat VSMC also had increased TGM2 expression and the calcification of MV on type I collagen could be inhibited with cystamine and accelerated by exogenous cross-linking of fibronectin or type I collagen with TGM2. Finally, the calcification of aorta rings from CKD rats in ex vivo cultures was inhibited with TGM2 inhibitor. Conclusion: These data demonstrate a role of TGM2 in the pathogenesis of vascular calcification in CKD through enhancement of MV-ECM calcification.

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Section: Methodsmentioning

confidence: 99%

Transglutaminase 2 Accelerates Vascular Calcification in Chronic Kidney Disease

et al. 2013

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“…Choi et al [102] showed good bioavailability of 3-halo-4,5-dihydroisoxazoles in mice with efficient TG2 inhibition and low toxicity. However, in a more recent study the compound failed to affect TG2 activity in neuroblastoma-derived SH-SY5Y cells, whereas the proteolytically stable gluten peptide analog Z-DON-Val-Pro-LeuOMe (ZDON) induced almost complete inhibition of TG2 activity [104]. Two dihydroisoxazole derivatives, namely the irreversible TG2-specific small-molecule inhibitor KCC009 ((S)-[3-(4-hydroxyphenyl)-2-N-(phenylmethyloxycarbonyl)aminopropanoic acid N¢-(3¢-bromo-4¢,5¢-dihydro-5¢-isoxalyl)methylamide) and ERW1041E (2-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid quinolin-3-ylmethyl ester), also show great potential [105].…”

Section: Tg2 Inhibitorsmentioning

confidence: 98%

Transglutaminase as a therapeutic target for celiac disease

Sulic

Kurppa

Rauhavirta

et al. 2014

Expert Opinion on Therapeutic Targets

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Activation of TG2 in the intestinal mucosa is central in celiac disease pathogenesis and researchers have therefore suggested TG2 inhibitors as a potential therapeutic approach. However, a prerequisite for such a drug is that it should be specific for TG2 and not affect the activity of other members of the transglutaminase family. Such compounds have already been introduced and tested in vitro, but a major obstacle to further development is the lack of a well-defined animal model for celiac disease. Nonetheless, with encouraging results in preclinical studies clinical trials with TG2 inhibitors are eagerly awaited.

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“…When treated with all-transretinoic acid (RA), SH-SY5Y cells stop dividing and undergo neuronal differentiation [23] . In particular, these cells overexpress tTG protein [9,24] . These properties make the cell line suitable to assess the effects of enhanced tTG expression in neurodegenerative diseases.…”

Section: Original Articlementioning

confidence: 99%

Inhibition of tissue transglutaminase promotes Aβ-induced apoptosis in SH-SY5Y cells

2016

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Aim: Tissue transglutaminase (tTG) catalyzes proteins, including β-amyloid (Aβ), to cross-link as a γ-glutamyl-ε-lysine structure isopeptide, which is highly resistant to proteolysis. Thus, tTG plays an important role in protein accumulation in Alzheimer's disease (AD). In the present study, we examined the effect of an irreversible tTG inhibitor, NTU283, on Aβ mimic-induced AD pathogenesis in SH-SY5Y cells. Methods: Western blot and in-cell Western analyses were used to detect tTG and isopeptide (representing the enzyme activity of tTG) protein levels. Moreover, Hoechst and PI co-staining was performed, and caspase-3 and caspase-7 activities and the Bax/Bcl-2 ratio were determined to evaluate the effects of NTU283 on apoptosis. Results:The results confirmed that tTG activity was inhibited by NTU283 20-500 μmol/L in a concentration-dependent manner in SH-SY5Y cells. Contrary to our expectations, however, the isopeptide bonds were increased when cells were co-treated with Aβ and NTU283. In addition, NTU283 alone did not induce apoptosis in SH-SY5Y cells. However, when co-applied with Aβ, NTU283 promoted rather than inhibited Aβ-induced apoptosis. Consistent with the apoptotic rate, pretreating cells with different concentrations of NTU283 and Aβ significantly increased the activities of caspase-3 and caspase-7 as well as the ratio of Bax/Bcl-2. Conclusion: Irreversible inhibition of tTG activity did not block but rather promoted Aβ-induced apoptosis, which indicated that tTG has complex functions in AD pathogenesis.

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Blockade of enzyme activity inhibits tissue transglutaminase-mediated transamidation of α-synuclein in a cellular model of Parkinson's disease

Cited by 34 publications

References 60 publications

Transglutaminase 2 Accelerates Vascular Calcification in Chronic Kidney Disease

Transglutaminase 2 Accelerates Vascular Calcification in Chronic Kidney Disease

Transglutaminase as a therapeutic target for celiac disease

Inhibition of tissue transglutaminase promotes Aβ-induced apoptosis in SH-SY5Y cells

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