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Transglutaminase 2 exacerbates α‐synuclein toxicity in mice and yeast
Author(s) -
Grosso Hilary,
Woo JongMin,
Lee KangWoo,
Im JooYoung,
Masliah Eliezer,
Junn Eunsung,
Mouradian M. Maral
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-251413
Subject(s) - toxicity , tissue transglutaminase , thioflavin , alpha synuclein , synucleinopathies , genetically modified mouse , in vivo , biology , amyloid (mycology) , protein aggregation , microglia , transgene , biochemistry , microbiology and biotechnology , alzheimer's disease , chemistry , medicine , inflammation , parkinson's disease , immunology , enzyme , disease , gene , botany , organic chemistry
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.—Grosso, H., Woo, J.‐M., Lee, K.W., Im, J.‐Y., Masliah, E., Junn, E., Mouradian, M. M., Transglutaminase 2 exacerbates α‐synuclein toxicity in mice and yeast. FASEB J. 28, 4280–4291 (2014). www.fasebj.org