ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2014
Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 35 citations in OpenAlex.
- The cross-linking activity of transglutaminase 2 drives α-Synuclein pathology in synucleinopathy models.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Protein phosphatase 2A methylation state impacts α-synucleinopathy in mouse models.Cell death discovery · 2026Article
- Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.Frontiers in aging neuroscience · 2026Review
- Dose-Ranging Effects of the Intracerebral Administration of Atsttrin in Experimental Model of Parkinson's Disease Induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Mice.Molecular neurobiology · 2024Article
- Posttranslational Modifications ofPharmacological reviews · 2024Review
- Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn ("line 61") Mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Review
- Therapeutics in the Pipeline TargetingPharmacological reviews · 2022Review
- Targeting transglutaminase 2 as a potential disease modifying therapeutic strategy for synucleinopathies.Neural regeneration research · 2021Article
- Article
- Apoptosis signal regulating kinase 1 deletion mitigates α-synuclein pre-formed fibril propagation in mice.Neurobiology of aging · 2020Article
- Effects of α-Synuclein Monomers Administration in the Gigantocellular Reticular Nucleus on Neurotransmission in Mouse Model.Neurochemical research · 2019Article
- Transglutaminase 2 has opposing roles in the regulation of cellular functions as well as cell growth and death.Cell death & disease · 2016Review
- Glia and alpha-synuclein in neurodegeneration: A complex interaction.Neurobiology of disease · 2016Review
- Seeking a mechanism for the toxicity of oligomeric α-synuclein.Biomolecules · 2015Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
α-Synuclein is a key pathogenic protein that aggregates in hallmark lesions in Parkinson's disease and other α-synucleinopathies. Prior in vitro studies demonstrated that it is a substrate for cross-linking by transglutaminase 2 (TG2) into higher-order species. Here we investigated whether this increased aggregation occurs in vivo and whether TG2 exacerbates α-synuclein toxicity in Mus musculus and Saccharomyces cerevisiae. Compared with α-synuclein transgenic (Syn(Tg)) mice, animals double transgenic for human α-synuclein and TG2 (TG2(Tg)/Syn(Tg)) manifested greater high-molecular-weight insoluble species of α-synuclein in brain lysates and developed α-synuclein aggregates in the synaptic vesicle fraction. In addition, larger proteinase K-resistant aggregates developed, along with increased thioflavin-S-positive amyloid fibrils. This correlated with an exaggerated neuroinflammatory response, as seen with more astrocytes and microglia. Further neuronal damage was suggested by greater morphological disruption of nerve fibers and a trend toward decreased c-Fos immunoreactive neurons. Finally, the performance of TG2(Tg)/Syn(Tg) animals on motor behavioral tasks was worse relative to Syn(Tg) mice. Greater toxicity of α-synuclein was also demonstrated in yeast cells coexpressing TG2. Our findings demonstrate that TG2 promotes the aggregation of α-synuclein in vivo and that this is associated with aggravated toxicity of α-synuclein and its downstream neuropathologic consequences.
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