title: Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast.
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.
authors: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and.
authors: Hilary
authors: H
authors: Grosso
authors: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and.
authors: Jong-Min
authors: JM
authors: Woo
authors: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and.
authors: Kang-Woo
authors: KW
authors: Lee
authors: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and.
authors: Joo-Young
authors: JY
authors: Im
authors: Department of Neurosciences, School of Medicine, University of California-San Diego, La Jolla, California, USA.
authors: Eliezer
authors: E
authors: Masliah
authors: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and.
authors: Eunsung
authors: E
authors: Junn
authors: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and m.mouradian@rutgers.edu.
authors: M Maral
authors: MM
authors: Mouradian
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Parkinson's disease; neurodegeneration; protein misfolding