ArticleThe Journal of biological chemistry2009
Dissecting the mechanisms of tissue transglutaminase-induced cross-linking of alpha-synuclein: implications for the pathogenesis of Parkinson disease.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 48 citations in OpenAlex.
- Posttranslational Modifications ofPharmacological reviews · 2024Review
- Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors.Cells · 2024Review
- Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis.Aging and disease · 2024Review
- Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- A guide to selecting high-performing antibodies for Protein-glutamine gamma-glutamyltransferase 2 (TGM2) for use in western blot, immunoprecipitation and immunofluorescence.F1000Research · 2024Article
- Cross-Linked α-Synuclein as Inhibitor of Amyloid Formation.International journal of molecular sciences · 2023Article
- Absence of tissue transglutaminase reduces amyloid-beta pathology in APP23 mice.Neuropathology and applied neurobiology · 2022Article
- Role of TG2 and TGF-βOncology letters · 2020Article
- Review
- Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade?Journal of Parkinson's disease · 2016Review
- Parkinson disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo.The Journal of biological chemistry · 2015Article
- Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2014Article
- Keratin 8 phosphorylation regulates its transamidation and hepatocyte Mallory-Denk body formation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2012Article
- Tissue transglutaminase-mediated glutamine deamidation of beta-amyloid peptide increases peptide solubility, whereas enzymatic cross-linking and peptide fragmentation may serve as molecular triggers for rapid peptide aggregation.The Journal of biological chemistry · 2011Article
- Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain.Brain pathology (Zurich, Switzerland) · 2011Article
- Transglutaminase-mediated intramolecular cross-linking of membrane-bound alpha-synuclein promotes amyloid formation in Lewy bodies.The Journal of biological chemistry · 2009Article
- Transglutaminase activation in neurodegenerative diseases.Future neurology · 2009Article
- E46K Parkinson's-linked mutation enhances C-terminal-to-N-terminal contacts in alpha-synuclein.Journal of molecular biology · 2009Article
- Using mass spectrometry-based methods to understand amyloid formation and inhibition of alpha-synuclein and amyloid beta.Mass spectrometry reviewsReview
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tissue transglutaminase (tTG) has been implicated in the pathogenesis of Parkinson disease (PD). However, exactly how tTG modulates the structural and functional properties of alpha-synuclein (alpha-syn) and contributes to the pathogenesis of PD remains unknown. Using site-directed mutagenesis combined with detailed biophysical and mass spectrometry analyses, we sought to identify the exact residues involved in tTG-catalyzed cross-linking of wild-type alpha-syn and alpha-syn mutants associated with PD. To better understand the structural consequences of each cross-linking reaction, we determined the effect of tTG-catalyzed cross-linking on the oligomerization, fibrillization, and membrane binding of alpha-syn in vitro. Our findings show that tTG-catalyzed cross-linking of monomeric alpha-syn involves multiple cross-links (specifically 2-3). We subjected tTG-catalyzed cross-linked monomeric alpha-syn composed of either wild-type or Gln --> Asn mutants to sequential proteolysis by multiple enzymes and peptide mapping by mass spectrometry. Using this approach, we identified the glutamine and lysine residues involved in tTG-catalyzed intramolecular cross-linking of alpha-syn. These studies demonstrate for the first time that Gln(79) and Gln(109) serve as the primary tTG reactive sites. Mutating both residues to asparagine abolishes tTG-catalyzed cross-linking of alpha-syn and tTG-induced inhibition of alpha-syn fibrillization in vitro. To further elucidate the sequence and structural basis underlying these effects, we identified the lysine residues that form isopeptide bonds with Gln(79) and Gln(109). This study provides mechanistic insight into the sequence and structural basis of the inhibitory effects of tTG on alpha-syn fibrillogenesis in vivo, and it sheds light on the potential role of tTG cross-linking on modulating the physiological and pathogenic properties of alpha-syn.
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